Isoindolinone kinase inhibitors

ABSTRACT

Compounds having the formula 
                         
are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/475,110, filed Jun. 2, 2003.

TECHNICAL FIELD

The present invention relates to compounds which are useful forinhibiting protein tyrosine kinases, methods of making the compounds,compositions containing the compounds, and methods of treatment usingthe compounds.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (PTKs) are enzymes which catalyse thephosphorylation of specific tyrosine residues in cellular proteins. Thispost-translational modification of these substrate proteins, oftenenzymes themselves, acts as a molecular switch regulating cellproliferation, activation, or differentiation. Aberrant or excessive PTKactivity has been observed in many disease states including benign andmalignant proliferative disorders as well as diseases resulting frominappropriate activation of the immune system (e.g., autoimmunedisorders), allograft rejection, and graft vs. host disease. Inaddition, endothelial-cell specific receptor PTKs such as KDR and Tie-2mediate the angiogenic process, and are thus involved in supporting theprogression of cancers and other diseases involving inappropriatevascularization (e.g., diabetic retinopathy, choroidalneovascularization due to age-related macular degeneration, psoriasis,arthritis, retinopathy of prematurity, and infantile hemangiomas).

The identification of effective small compounds which specificallyinhibit signal transduction and cellular proliferation by modulating theactivity of tyrosine kinases to regulate and modulate abnormal orinappropriate cell proliferation, differentiation, or metabolism istherefore desirable. In particular, the identification of methods andcompounds that specifically inhibit the function of a tyrosine kinasewhich is essential for angiogenic processes or the formation of vascularhyperpermeability leading to edema, ascites, effusions, exudates, andmacromolecular extravasation and matrix deposition as well as associateddisorders would be beneficial.

SUMMARY OF THE INVENTION

In its principle embodiment, the present invention provides a compoundof formula (I)

or a therapeutically acceptable salt thereof, wherein

R¹ is selected from the group consisting of hydrogen and alkyl;

R² is selected from the group consisting of hydrogen, alkoxy,alkoxyalkoxy, alkyl, carboxyalkoxy, carboxyalkyl, halo, haloalkyl,heterocyclylalkoxy, hydroxy, nitro, and —NR^(c)R^(d); and

one of R³ and R⁴ is A-X-R⁵ and the other is hydrogen; wherein A-X-R⁵ isdrawn with its left end attached to the parent molecular moiety;

R⁵ is selected from the group consisting of aryl, heteroaryl, andheterocyclyl;

A is selected from the group consisting of aryl and heteroaryl, whereinthe aryl and the heteroaryl are optionally substituted with one or twosubstituents independently selected from the group consisting of alkyl,halo, haloalkoxy, and haloalkyl; and

X is selected from the group consisting of O, NR^(a),N(R^(a))C(S)N(R^(b)), (CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n),CH₂C(O)N(R^(a)), and N(R^(a))C(O), wherein R^(a) and R^(b) areindependently selected from the group consisting of hydrogen and alkyl,m and n are independently 0 or 1, and wherein each group is drawn withits left end attached to A and its right end attached to R⁵.

In a preferred embodiment, the present invention discloses a compound offormula (I) where R¹ is hydrogen.

In a preferred embodiment, the present invention discloses a compound offormula (I) where R³ is A-X-R⁵ and R⁴ is hydrogen.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, and X isselected from the group consisting of O, NR^(a), N(R^(a))C(S)N(R^(b)),CH₂C(O)N(R^(a)), and N(R^(a))C(O).

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, and X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n).

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R^(a) and R^(b) are hydrogen,and m and n are 0.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), and R² is other than hydrogen.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R² is hydrogen, and R⁵ isselected from the group consisting of aryl and heteroaryl, wherein thearyl and the heteroaryl are unsubstituted.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R² is hydrogen, and R⁵ isselected from the group consisting of aryl and heteroaryl, wherein thearyl and the heteroaryl are monosubstituted.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R² is hydrogen, R⁵ is selectedfrom the group consisting of aryl and heteroaryl, wherein the aryl andthe heteroaryl are monosubstituted, and A is selected from the groupconsisting of aryl and heteroaryl, wherein the aryl and the heteroarylare unsubstituted.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R² is hydrogen, R⁵ is selectedfrom the group consisting of aryl and heteroaryl, wherein the aryl andthe heteroaryl are monosubstituted, and A is selected from the groupconsisting of aryl and heteroaryl, wherein the aryl and the heteroarylare monosubstituted.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R² is hydrogen, and R⁵ isselected from the group consisting of aryl and heteroaryl, wherein thearyl and the heteroaryl are disubstituted.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R² is hydrogen, R⁵ is selectedfrom the group consisting of aryl and heteroaryl, wherein the aryl andthe heteroaryl are disubstituted, and A is selected from the groupconsisting of aryl and heteroaryl, wherein the aryl and the heteroarylare unsubstituted.

In another preferred embodiment, the present invention discloses acompound of formula (I) where R³ is A-X-R⁵, R⁴ is hydrogen, X is(CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), R² is hydrogen, R⁵ is selectedfrom the group consisting of aryl and heteroaryl, wherein the aryl andthe heteroaryl are disubstituted, and A is selected from the groupconsisting of aryl and heteroaryl, wherein the aryl and the heteroarylare monosubstituted.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a therapeuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment, the present invention provides a method forinhibiting protein kinase in a patient in recognized need of suchtreatment comprising administering to the patient a therapeuticallyacceptable amount of a compound of formula (I), or a therapeuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method fortreating cancer in a patient in recognized need of such treatmentcomprising administering to the patient a therapeutically acceptableamount of a compound of formula (I), or a therapeutically acceptablesalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

All publications, issued patents, and patent applications cited hereinare hereby incorporated by reference.

As used in the present specification the following terms have themeanings indicated:

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkoxy,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through another alkoxy group.

The term “alkoxyalkoxyalkyl,” as used herein, refers to an alkoxyalkoxygroup attached to the parent molecular moiety through an alkyl group.

The term “alkoxyalkoxyalkylcarbonyl,” as used herein, refers to analkoxyalkoxyalkyl group attached to the parent molecular moiety througha carbonyl group.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through an alkyl group.

The term “alkoxyalkylcarbonyl,” as used herein, refers to an alkoxyalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon containing from one toten carbon atoms.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylsulfanyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfur atom.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicor tricyclic fused ring system wherein one or more of the fused rings isa phenyl group. Bicyclic fused ring systems are exemplified by a phenylgroup fused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Tricyclic fused ring systems are exemplified by a bicyclic fused ringsystem fused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Representative examples of aryl include, but are not limited to,anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl,and tetrahydronaphthyl. The aryl groups of the present invention can beoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, a second arylgroup, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl, carboxy, cyano,cyanoalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, hydroxy, nitro, oxo, and —NR^(c)R^(d),wherein the second aryl group, the aryl part of the arylalkoxy, thearylalkyl, the aryloxy, and the arylsulfanyl, the heteroaryl, theheteroaryl part of the heteroarylalkyl, the heterocyclyl, and theheterocyclyl part of the heterocyclylalkyl can be further optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy,haloalkyl, hydroxy, and nitro.

The term “arylalkoxy,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkoxy group.

The term “arylalkoxycarbonyl,” as used herein, refers to an arylalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkyl group.

The term “arylalkylcarbonyl,” as used herein, refers to an arylalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “aryloxy,” as used herein, refers to an aryl group attached tothe parent molecular moiety through an oxygen atom.

The term “arylsulfanyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a sulfur atom.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “carboxyalkoxy,” as used herein, refers to a carboxy groupattached to the parent molecular moiety through an alkoxy group.

The term “carboxyalkyl,” as used herein, refers to a carboxy groupattached to the parent molecular moiety through an alkyl group.

The term “cyano,” as used herein, refers to —CN.

The term “cyanoalkyl,” as used herein, refers to a cyano group attachedto the parent molecular moiety through an alkyl group.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic cyclicor bicyclic ring system having three to ten carbon atoms and one tothree rings, wherein each five-membered ring has one double bond, eachsix-membered ring has one or two double bonds, each seven- andeight-membered ring has one to three double bonds, and each nine-toten-membered ring has one to four double bonds. Examples of cycloalkenylgroups include, but are not limited to, cyclohexenyl,octahydronaphthalenyl, and norbornylenyl.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,bicyclic, or tricyclic hydrocarbon ring system having three to twelvecarbon atoms. Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, and adamantyl.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, orI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “heteroaryl,” as used herein, refers to an aromatic five- orsix-membered ring where at least one atom is selected from the groupconsisting of N, O, and S, and the remaining atoms are carbon. Thefive-membered rings have two double bonds, and the six-membered ringshave three double bonds. The heteroaryl groups are connected to theparent molecular group through a substitutable carbon or nitrogen atomin the ring. The term “heteroaryl” also includes bicyclic systems wherea heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkenylgroup, as defined herein, a monocyclic cycloalkyl group, as definedherein, a heterocyclyl group, as defined herein, or an additionalheteroaryl group; and tricyclic systems where a bicyclic system is fusedto a phenyl group, a monocyclic cycloalkyl group, as defined herein, aheterocyclyl group, as defined herein, or an additional heteroarylgroup. Heteroaryls are exemplified by benzothienyl, benzoxadiazolyl,cinnolinyl, dibenzofuranyl, furanyl, imidazolyl, indazolyl, indolyl,isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyrrolyl, quinolinyl, triazinyl, and the like. The heteroaryl groups ofthe present invention can be optionally substituted with one, two,three, four, or five substituents independently selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfanyl, aryl, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl,carboxy, cyano, cyanoalkyl, halo, haloalkoxy, haloalkyl, a secondheteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy,nitro, oxo, and —NR^(c)R^(d), wherein the aryl, the aryl part of thearylalkoxy, the arylalkyl, the aryloxy, and the arylsulfanyl, the secondheteroaryl group, the heteroaryl part of the heteroarylalkyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl can befurther optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy,haloalkyl, hydroxy, and nitro.

The term “heteroarylalkyl,” as used herein, refers to a heteroaryl groupattached to the parent molecular moiety through an alkyl group.

The term “heteroarylcarbonyl,” as used herein, refers to a heteroarylgroup attached to the parent molecular moiety through a carbonyl group.

The term “heterocyclyl,” as used herein, refers to cyclic, non-aromatic,five-, six-, or seven-membered rings containing at least one atomselected from the group consisting of oxygen, nitrogen, and sulfur. Thefive-membered rings have zero or one double bonds and the six- andseven-membered rings have zero, one, or two double bonds. Theheterocyclyl groups of the invention are connected to the parentmolecular group through a substitutable carbon or nitrogen atom in thering. The term “heterocyclyl” also includes bicyclic systems where aheterocyclyl ring is fused to a phenyl group, a monocyclic cycloalkenylgroup, as defined herein, a monocyclic cycloalkyl group, as definedherein, or an additional monocyclic heterocyclyl group; and tricyclicsystems where a bicyclic system is fused to a phenyl group, a monocycliccycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, asdefined herein, or an additional monocyclic heterocyclyl group. Examplesof heterocyclyl groups include, but are not limited to, benzothiazolyl,dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, and thiomorpholinyl. The heterocyclylgroups of the present invention can be optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfanyl, aryl, arylalkoxy, arylalkyl, aryloxy, arylsulfanyl,carboxy, cyano, cyanoalkyl, halo, haloalkoxy, haloalkyl, heteroaryl,heteroarylalkyl, a second heterocyclyl group, heterocyclylalkyl,hydroxy, nitro, oxo, and —NR^(c)R^(d), wherein the aryl, the aryl partof the arylalkoxy, the arylalkyl, the aryloxy, and the arylsulfanyl, theheteroaryl, the heteroaryl part of the heteroarylalkyl, the secondheterocyclyl group, and the heterocyclyl part of the heterocyclylalkylcan be further optionally substituted with one, two, three, four, orfive substituents independently selected from the group consisting ofalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, and nitro.

The term “heterocyclylalkoxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an alkoxy group.

The term “heterocyclylalkyl,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an alkyl group.

The term “heterocyclylcarbonyl,” as used herein, refers to aheterocyclyl group attached to the parent molecular moiety through acarbonyl group.

The term “hydroxy,” as used herein, refers to —OH.

The term “nitro,” as used herein, refers to —NO₂.

The term “oxo,” as used herein, refers to ═O.

The term “—NR^(c)R^(d),” as used herein, refers to two groups, R^(c) andR^(d), which are appended to the parent molecular moiety through anitrogen atom. R^(c) and R^(d) are each independently selected from thegroup consisting of hydrogen, alkoxyalkyl, alkoxyalkoxyalkylcarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryl,arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl,heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl,heterocyclylalkyl, heterocyclylcarbonyl, and —C(O)(CH₂)_(n)NR^(e)R^(f),wherein n is 0, 1, or 2 and R^(e) and R^(f) are independently selectedfrom the group consisting of hydrogen and alkyl, and wherein the aryl,the aryl part of the arylalkoxycarbonyl, the arylalkyl, thearylalkylcarbonyl, and the arylcarbonyl, the heteroaryl, the heteroarylpart of the heteroarylalkyl and the heteroarylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylcarbonyl canbe optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy,haloalkyl, and nitro.

The compounds of the present invention can exist as therapeuticallyacceptable salts. The term “therapeutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent invention which are water or oil-soluble or dispersible, whichare suitable for treatment of diseases without undue toxicity,irritation, and allergic response; which are commensurate with areasonable benefit/risk ratio, and which are effective for theirintended use. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting a suitablenitrogen atom with a suitable acid. Representative acid addition saltsinclude acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate,trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Also, suitable nitrogen atoms inthe compounds of the present invention can be quaternized with methyl,ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl,diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, andsteryl chlorides, bromides, and iodides; and benzyl and phenethylbromides. Examples of acids which can be employed to formtherapeutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

The present compounds can also exist as therapeutically acceptableprodrugs. The term “therapeutically acceptable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use. The term “prodrug,” refers tocompounds which are rapidly transformed in vivo to parent compounds offormula (I) for example, by hydrolysis in blood.

In accordance with methods of treatment and pharmaceutical compositionsof the invention, the compounds can be administered alone or incombination with other anticancer agents. When using the compounds, thespecific therapeutically effective dose level for any particular patientwill depend upon factors such as the disorder being treated and theseverity of the disorder; the activity of the particular compound used;the specific composition employed; the age, body weight, general health,sex, and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the compound employed; theduration of treatment; and drugs used in combination with orcoincidently with the compound used. The compounds can be administeredorally, parenterally, osmotically (nasal sprays), rectally, vaginally,or topically in unit dosage formulations containing carriers, adjuvants,diluents, vehicles, or combinations thereof. The term “parenteral”includes infusion as well as subcutaneous, intravenous, intramuscular,and intrasternal injection.

Parenterally administered aqueous or oleaginous suspensions of thecompounds can be formulated with dispersing, wetting, or suspendingagents. The injectable preparation can also be an injectable solution orsuspension in a diluent or solvent. Among the acceptable diluents orsolvents employed are water, saline, Ringer's solution, buffers,monoglycerides, diglycerides, fatty acids such as oleic acid, and fixedoils such as monoglycerides or diglycerides.

The anticancer effect of parenterally administered compounds can beprolonged by slowing their absorption. One way to slow the absorption ofa particular compound is administering injectable depot forms comprisingsuspensions of crystalline, amorphous, or otherwise water-insolubleforms of the compound. The rate of absorption of the compound isdependent on its rate of dissolution which is, in turn, dependent on itsphysical state. Another way to slow absorption of a particular compoundis administering injectable depot forms comprising the compound as anoleaginous solution or suspension. Yet another way to slow absorption ofa particular compound is administering injectable depot forms comprisingmicrocapsule matrices of the compound trapped within liposomes,microemulsions, or biodegradable polymers such aspolylactide-polyglycolide, polyorthoesters or polyanhydrides. Dependingon the ratio of drug to polymer and the composition of the polymer, therate of drug release can be controlled.

Transdermal patches can also provide controlled delivery of thecompounds. The rate of absorption can be slowed by using ratecontrolling membranes or by trapping the compound within a polymermatrix or gel. Conversely, absorption enhancers can be used to increaseabsorption.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In these solid dosage forms, the activecompound can optionally comprise diluents such as sucrose, lactose,starch, talc, silicic acid, aluminum hydroxide, calcium silicates,polyamide powder, tableting lubricants, and tableting aids such asmagnesium stearate or microcrystalline cellulose. Capsules, tablets andpills can also comprise buffering agents, and tablets and pills can beprepared with enteric coatings or other release-controlling coatings.Powders and sprays can also contain excipients such as talc, silicicacid, aluminum hydroxide, calcium silicate, polyamide powder, ormixtures thereof. Sprays can additionally contain customary propellantssuch as chlorofluorohydrocarbons or substitutes therefore.

Liquid dosage forms for oral administration include emulsions,microemulsions, solutions, suspensions, syrups, and elixirs comprisinginert diluents such as water. These compositions can also compriseadjuvants such as wetting, emulsifying, suspending, sweetening,flavoring, and perfuming agents.

Topical dosage forms include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and transdermal patches. Thecompound is mixed under sterile conditions with a carrier and any neededpreservatives or buffers. These dosage forms can also include excipientssuch as animal and vegetable fats, oils, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.Suppositories for rectal or vaginal administration can be prepared bymixing the compounds with a suitable non-irritating excipient such ascocoa butter or polyethylene glycol, each of which is solid at ordinarytemperature but fluid in the rectum or vagina. Ophthalmic formulationscomprising eye drops, eye ointments, powders, and solutions are alsocontemplated as being within the scope of this invention.

The total daily dose of the compounds administered to a host in singleor divided doses can be in amounts from about 0.1 to about 200 mg/kgbody weight or preferably from about 0.25 to about 100 mg/kg bodyweight. Single dose compositions can contain these amounts orsubmultiples thereof to make up the daily dose.

Preferred compounds of the present invention are compounds of formula(I) where R¹ is hydrogen, X is N(R^(a))C(O)N(R^(b)), and R^(a) and R^(b)are hydrogen.

Determination of Biological Activity

The in vitro potency of compounds in inhibiting these protein kinasesmay be determined by the procedures detailed below.

The potency of compounds can be determined by the amount of inhibitionof the phosphorylation of an exogenous substrate (e.g., syntheticpeptide (Z. Songyang et al., Nature. 373:536–539) by a test compoundrelative to control.

KDR Tyrosine Kinase Production Using Baculovirus System:

The coding sequence for the human KDR intra-cellular domain (aa789–1354)was generated through PCR using cDNAs isolated from HUVEC cells. Apoly-His6 sequence was introduced at the N-terminus of this protein aswell. This fragment was cloned into transfection vector pVL1393 at theXba 1 and Not 1 site. Recombinant baculovirus (BV) was generated throughco-transfection using the BaculoGold Transfection reagent (PharMingen).Recombinant BV was plaque purified and verified through Westernanalysis. For protein production, SF-9 cells were grown in SF-900-IImedium at 2×106/mL, and were infected at 0.5 plaque forming units percell (MOI). Cells were harvested at 48 hours post infection.

Purification of KDR

SF-9 cells expressing (His)₆KDR(aa789–1354) were lysed by adding 50 mlof Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10%glycerol, 1% Triton X-100, 1 mM PMSF, 10 μg/ml aprotinin, 1 μg/mlleupeptin) to the cell pellet from 1 L of cell culture. The lysate wascentrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4 EC.The cell lysate was applied to a 5 ml NiCl₂ chelating sepharose column,equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCl. KDR was eluted usingthe same buffer containing 0.25 M imidazole. Column fractions wereanalyzed using SDS-PAGE and an ELISA assay (below) which measures kinaseactivity. The purified KDR was exchanged into 25 mM HEPES, pH7.5, 25 mMNaCl, 5 mM DTT buffer and stored at −80 EC.

Compounds of the present invention inhibited KDR at IC50's between about0.007 μM and about 50 μM. Preferred compounds inhibited KDR at IC50'sbetween about 0.007 μM and about 0.5 μM. Most preferred compoundsinhibited KDR at IC50's of between about 0.007 μM and about 0.1 μM.

Human Tie-2 Kinase Production and Purification

The coding sequence for the human Tie-2 intra-cellular domain(aa775–1124) was generated through PCR using cDNAs isolated from humanplacenta as a template. A poly-His₆ sequence was introduced at theN-terminus and this construct was cloned into transfection vector pVL1939 at the Xba 1 and Not 1 site. Recombinant BV was generated throughco-transfection using the BaculoGold Transfection reagent (PharMingen).Recombinant BV was plaque purified and verified through Westernanalysis. For protein production, SF-9 insect cells were grown inSF-900-II medium at 2×106/ml, and were infected at MOI of 0.5.Purification of the His-tagged kinase used in screening was analogous tothat described for KDR.

Human Flt-1 Tyrosine Kinase Production and Purification

The baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles,Calif.) was used. A nucleotide sequence encoding poly-His6 was placed 5′to the nucleotide region encoding the entire intracellular kinase domainof human Flt-1 (amino acids 786–1338). The nucleotide sequence encodingthe kinase domain was generated through PCR using cDNA librariesisolated from HUVEC cells. The histidine residues enabled affinitypurification of the protein as a manner analogous to that for KDR andZAP70. SF-9 insect cells were infected at a 0.5 multiplicity andharvested 48 hours post infection.

EGFR Tyrosine Kinase Source

EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 μl) and theEGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat# PF011-100).

Protein Kinase Source

Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may becommercially obtained (e.g., from Upstate Biotechnology Inc. (SaranacLake, N.Y.) and Santa Cruz Biotechnology Inc. (Santa Cruz, Calif.)) orpurified from known natural or recombinant sources using conventionalmethods.

Enzyme Linked Immunosorbent Assay (ELISA) for PTKs

Enzyme linked immunosorbent assays (ELISA) were used to detect andmeasure the presence of tyrosine kinase activity. The ELISA wereconducted according to known protocols which are described in, forexample, Voller, et al., 1980, “Enzyme-Linked lmmunosorbent Assay,” In:Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp359–371 Am. Soc. of Microbiology, Washington, D.C.

The disclosed protocol was adapted for determining activity with respectto a specific PTK. For example, preferred protocols for conducting theELISA experiments is provided below. Adaptation of these protocols fordetermining a compound's activity for other members of the receptor PTKfamily, as well as non-receptor tyrosine kinases, are well within theabilities of those in the art. For purposes of determining inhibitorselectivity, a universal PTK substrate (e.g., random copolymer ofpoly(Glu₄ Tyr), 20,000–50,000 MW) was employed together with ATP(typically 5 μM) at concentrations approximately twice the apparent Kmin the assay.

The following procedure was used to assay the inhibitory effect ofcompounds of this invention on KDR, Flt-1, Flt-4, Tie-1, Tie-2, EGFR,FGFR, PDGFR, IGF-1-R, c-Met, Lck, hck, Blk, Csk, Src, Lyn, fgr, Fyn andZAP70 tyrosine kinase activity:

Buffers and Solutions:

-   PGTPoly (Glu,Tyr) 4:1-   Store powder at −20° C. Dissolve powder in phosphate buffered saline    (PBS) for 50 mg/ml solution. Store 1 ml aliquots at −20° C. When    making plates dilute to 250 μg/ml in Gibco PBS. Reaction Buffer: 100    mM Hepes, 20 mM MgCl₂, 4 mM MnCl₂, 5 mM DTT, 0.02% BSA, 200 μM    NaVO₄, pH 7.10-   ATP: Store aliquots of 100 mM at −20° C. Dilute to 20 μM in water-   Washing Buffer: PBS with 0.1% Tween 20-   Antibody Diluting Buffer: 0.1% bovine serum albumin (BSA) in PBS-   TMB Substrate: mix TMB substrate and Peroxide solutions 9:1 just    before use or use K-Blue Substrate from Neogen-   Stop Solution: 1 M Phosphoric Acid    Procedure    1. Plate Preparation:

Dilute PGT stock (50 mg/ml, frozen) in PBS to a 250 μg/ml. Add 125 μlper well of Corning modified flat bottom high affinity ELISA plates(Corning #25805-96). Add 125 μl PBS to blank wells. Cover with sealingtape and incubate overnight 37° C. Wash 1× with 250 μl washing bufferand dry for about 2 hrs in 37° C. dry incubator. Store coated plates insealed bag at 4° C. until used.

2. Tyrosine Kinase Reaction:

-   Prepare inhibitor solutions at a 4× concentration in 20% DMSO in    water.-   Prepare reaction buffer-   Prepare enzyme solution so that desired units are in 50 μl, e.g. for    KDR make to 1 ng/μl for a total of 50 ng per well in the reactions.    Store on ice.-   Make 4× ATP solution to 20 μM from 100 mM stock in water. Store on    ice-   Add 50 μl of the enzyme solution per well (typically 5–50 ng    enzyme/well depending on the specific activity of the kinase)-   Add 25 μl 4× inhibitor-   Add 25 μl 4× ATP for inhibitor assay-   Incubate for 10 minutes at room temperature-   Stop reaction by adding 50 μl 0.05N HCl per well-   Wash plate-   Final Concentrations for Reaction: 5 μM ATP, 5% DMSO    3. Antibody Binding-   Dilute 1 mg/ml aliquot of PY20-HRP (Pierce) antibody(a    phosphotyrosine antibody)to 50 ng/ml in 0.1% BSA in PBS by a 2 step    dilution (100×, then 200×)-   Add 100 μl Ab per well. Incubate 1 hr at room temp. Incubate 1 hr at    4 C.-   Wash 4× plate    4. Color Reaction-   Prepare TMB substrate and add 100 μl per well-   Monitor OD at 650 nm until 0.6 is reached-   Stop with 1M Phosphoric acid. Shake on plate reader.-   Read OD immediately at 450 nm

Optimal incubation times and enzyme reaction conditions vary slightlywith enzyme preparations and are determined empirically for each lot.

For Lck, the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mMMnCl₂, 20 mM MgCl₂, 5 mM DTT, 0.2% BSA, 200 mM NaVO₄ under the analogousassay conditions.

Compounds of the invention may have therapeutic utility in the treatmentof diseases involving both identified, including those not mentionedherein, and as yet unidentified protein tyrosine kinases.

Cdc2 Source

The human recombinant enzyme and assay buffer may be obtainedcommercially (New England Biolabs, Beverly, Mass. USA) or purified fromknown natural or recombinant sources using conventional methods.

Cdc2 Assay

A protocol that can be used is that provided with the purchased reagentswith minor modifications. In brief, the reaction is carried out in abuffer consisting of 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mMDTT, 0.01% Brij, 5% DMSO and 10 mM MgCl₂ (commercial buffer)supplemented with fresh 300 μM ATP (31 μCi/ml) and 30 μg/ml histone typeIIIss final concentrations. A reaction volume of 80 μL, containing unitsof enzyme, is run for 20 minutes at 25 degrees C. in the presence orabsence of inhibitor. The reaction is terminated by the addition of 120μL of 10% acetic acid. The substrate is separated from unincorporatedlabel by spotting the mixture on phosphocellulose paper, followed by 3washes of 5 minutes each with 75 mM phosphoric acid. Counts are measuredby a betacounter in the presence of liquid scintillant.

PKC Kinase Source

The catalytic subunit of PKC may be obtained commercially (Calbiochem).

PKC Kinase Assay

A radioactive kinase assay is employed following a published procedure(Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A.,Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166,1220–1227 (1990)). Briefly, all reactions are performed in a kinasebuffer consisting of 50 mM Tris-HCl pH7.5, 10 mM MgCl₂, 2 mM DTT, 1 mMEGTA, 100 μM ATP, 8 μM peptide, 5% DMSO and ³³P ATP (8 Ci/mM). Compoundand enzyme are mixed in the reaction vessel and the reaction isinitiated by addition of the ATP and substrate mixture. Followingtermination of the reaction by the addition of 10 μL stop buffer (5 mMATP in 75 mM phosphoric acid), a portion of the mixture is spotted onphosphocellulose filters. The spotted samples are washed 3 times in 75mM phosphoric acid at room temperature for 5 to 15 minutes.Incorporation of radiolabel is quantified by liquid scintillationcounting.

Erk2 Enzyme Source

The recombinant murine enzyme and assay buffer may be obtainedcommercially (New England Biolabs, Beverly Mass. USA) or purified fromknown natural or recombinant sources using conventional methods.

Erk2 Enzyme Assay

In brief, the reaction is carried out in a buffer consisting of 50 mMTris pH 7.5, 1 nM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl₂(commercial buffer) supplemented with fresh 100 μM ATP (31 μCi/ml) and30 μM myelin basic protein under conditions recommended by the supplier.Reaction volumes and method of assaying incorporated radioactivity areas described for the PKC assay (vide supra).

Cellular Receptor PTK Assays

The following cellular assay was used to determine the level of activityand effect of the different compounds of the present invention onKDR/VEGFR2. Similar receptor PTK assays employing a specific ligandstimulus can be designed along the same lines for other tyrosine kinasesusing techniques well known in the art.

VEGF-Induced KDR Phosphorylation in Human Umbilical Vein EndothelialCells (HUVEC) as Measured by Western Blots:

1. HUVEC cells (from pooled donors) can be purchased from Clonetics (SanDiego, Calif.) and cultured according to the manufacturer directions.Only early passages (3–8) are used for this assay. Cells are cultured in100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth,England) using complete EBM media (Clonetics).

2. For evaluating a compound's inhibitory activity, cells aretrypsinized and seeded at 0.5–1.0×10⁵ cells/well in each well of 6-wellcluster plates (Costar; Cambridge, Mass.).

3. 3–4 days after seeding, plates are typically 90–100% confluent.Medium is removed from all the wells, cells are rinsed with 5–10 ml ofPBS and incubated 18–24 h with 5 ml of EBM base media with nosupplements added (i.e., serum starvation).

4. Serial dilutions of inhibitors are added in 1 ml of EBM media (25 μM,5 μM, or 1 μM final concentration to cells and incubated for one hour at37° C. Human recombinant VEGF₁₆₅ (R & D Systems) is then added to allthe wells in 2 ml of EBM medium at a final concentration of 50 ng/ml andincubated at 37° C. for 10 minutes. Control cells untreated or treatedwith VEGF only are used to assess background phosphorylation andphosphorylation induction by VEGF.

All wells are then rinsed with 5–10 ml of cold PBS containing 1 mMSodium Orthovanadate (Sigma) and cells are lysed and scraped in 200 μlof RIPA buffer (50 mM Tris-HCl) pH7, 150 mM NaCl, 1% NP-40, 0.25% sodiumdeoxycholate, 1 mM EDTA) containing protease inhibitors (PMSF 1 mM,aprotinin 1 μg/ml, pepstatin 1 μg/ml, leupeptin 1 μg/ml, Na vanadate 1mM, Na fluoride 1 mM) and 1 μg/ml of Dnase (all chemicals from SigmaChemical Company, St Louis, Mo.). The lysate is spun at 14,000 rpm for30 min, to eliminate nuclei.

Equal amounts of proteins are then precipitated by addition of cold (−20C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum ofovernight. Pellets are reconstituted in Laemli sample buffer containing5% -mercaptoethanol (BioRad; Hercules, Calif.) and boiled for 5 min. Theproteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5 mmNovex, San Deigo, Calif.) and transferred onto a nitrocellulose membraneusing the Novex system. After blocking with bovine serum albumin (3%),the proteins are probed overnight with anti-KDR polyclonal antibody(C20, Santa Cruz Biotechnology; Santa Cruz, Calif.) or withanti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology,Lake Placid, N.Y.) at 4 C. After washing and incubating for 1 hour withHRP-conjugated F(ab)₂ of goat anti-rabbit or goat-anti-mouse IgG thebands are visualized using the emission chemiluminescience (ECL) system(Amersham Life Sciences, Arlington Heights, Ill.).

In Vivo Uterine Edema Model

This assay measures the capacity of compounds to inhibit the acuteincrease in uterine weight in mice which occurs in the first few hoursfollowing estrogen stimulation. This early onset of uterine weightincrease is known to be due to edema caused by increased permeability ofuterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993),133:829–837) demonstrated a close temporal relationship ofestrogen-stimulated uterine edema with increased expression of VEGF mRNAin the uterus. These results have been confirmed by the use ofneutralizing monoclonal antibody to VEGF which significantly reduced theacute increase in uterine weight following estrogen stimulation (WO97/42187). Hence, this system can serve as a model for in vivoinhibition of VEGF signalling and the associated hyperpermeability andedema.

-   Materials: All hormones can be purchased from Sigma (St. Louis, Mo.)    or Cal Biochem (La Jolla, Calif.) as lyophilized powders and    prepared according to supplier instructions. Vehicle components    (DMSO, Cremaphor EL) can be purchased from Sigma (St. Louis, Mo.).    Mice (Balb/c, 8–12 weeks old) can be purchased from Taconic    (Germantown, N.Y.) and housed in a pathogen-free animal facility in    accordance with institutional Animal Care and Use Committee    Guidelines.-   Method:

Day 1: Balb/c mice are given an intraperitoneal (i.p.) injection of 12.5units of pregnant mare's serum gonadotropin (PMSG).

Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG) i.p.

Day 4: Mice are randomized and divided into groups of 5–10. Testcompounds are administered by i.p., i.v. or p.o. routes depending onsolubility and vehicle at doses ranging from 1–100 mg/kg. Vehiclecontrol group receive vehicle only and two groups are left untreated.

Thirty minutes later, experimental, vehicle and 1 of the untreatedgroups are given an i.p. injection of 17-estradiol (500 mg/kg). After2–3 hours, the animals are sacrificed by CO₂ inhalation. Following amidline incision, each uterus was isolated and removed by cutting justbelow the cervix and at the junctions of the uterus and oviducts. Fatand connective tissue were removed with care not to disturb theintegrity of the uterus prior to weighing (wet weight). Uteri areblotted to remove fluid by pressing between two sheets of filter paperwith a one liter glass bottle filled with water. Uteri are weighedfollowing blotting (blotted weight). The difference between wet andblotted weights is taken as the fluid content of the uterus. Mean fluidcontent of treated groups is compared to untreated or vehicle treatedgroups. Significance is determined by Student's test. Non-stimulatedcontrol group is used to monitor estradiol response.

Certain compounds of this invention which are inhibitors of angiogenicreceptor tyrosine kinases can also be shown active in a Matrigel implantmodel of neovascularization. The Matrigel neovascularization modelinvolves the formation of new blood vessels within a clear marble ofextracellular matrix implanted subcutaneously which is induced by thepresence of proangiogenic factor producing tumor cells (for examplessee: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519–528; Anat.Rec. (1997), 249(1), 63–73; Int. J. Cancer (1995), 63(5), 694–701; Vasc.Biol. (1995), 15(11), 1857-6). The model preferably runs over 3–4 daysand endpoints include macroscopic visual/image scoring ofneovascularization, microscopic microvessel density determinations, andhemoglobin quantitation (Drabkin method) following removal of theimplant versus controls from animals untreated with inhibitors. Themodel may alternatively employ bFGF or HGF as the stimulus.

The compounds of the present invention may be used in the treatment ofprotein kinase-mediated conditions, such as benign and neoplasticproliferative diseases and disorders of the immune system. Such diseasesinclude autoimmune diseases, such as rheumatoid arthritis, thyroiditis,type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory boweldisease, Crohn's disease, myasthenia gravis and systemic lupuserythematosus; psoriasis, organ transplant rejection (e.g,. kidneyrejection, graft versus host disease), benign and neoplasticproliferative diseases, human cancers such as lung, breast, stomach,bladder, colon, pancreatic, ovarian, prostate and rectal cancer andhematopoietic malignancies (leukemia and lymphoma), glioblastoma,infantile hemangioma, and diseases involving inappropriatevascularization (for example diabetic retinopathy, retinopathy ofprematurity, choroidal neovascularization due to age-related maculardegeneration, and infantile hemangiomas in human beings). Suchinhibitors may be useful in the treatment of disorders involving VEGFmediated edema, ascites, effusions, and exudates, including for examplemacular edema, cerebral edema, acute lung injury and adult respiratorydistress syndrome (ARDS). In addition, the compounds of the inventionmay be useful in the treatment of pulmonary hypertension, particularlyin patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg.2001, 122 (1), 65–73).

Synthetic Methods

Abbreviations which have been used in the descriptions of the scheme andthe examples that follow are: PPh₃ for triphenylphosphine, dba fordibenzylideneacetone, EDCI for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, DCC for1,3-dicyclohexylcarbodiimide, HOBT for 1-hydroxybenzotriazole, NBS forN-bromosuccinimide, THF for tetrahydrofuran, DME for1,2-dimethoxyethane, DMSO for dimethylsulfoxide, DMF forN,N-dimethylformamide, TFA for trifluroacetic acid, and DEAD for diethylazodicarboxylate.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. The groups A, X, R¹, R², R³, R⁴, and R⁵ areas defined above unless otherwise noted below.

This invention is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesinclude those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

As shown in Scheme 1, compounds of formula (2) (where X′ is Br or I) canbe treated with ammonium hydroxide to provide compounds of formula (3).Compounds of formula (3) can be converted to compounds of formula (4) bytreatment with an organometallic coupling partner (M-A-NH₂, where M is ametal such as a boronic acid, boronic ester, or alkyl stannane) in thepresence of a palladium catalyst and optional base. Examples ofpalladium catalysts include Pd(PPh₃)₄, PdCl₂(PPh₃)₂, and Pd₂(dba)₃ witha ligand such as PPh₃. Representative bases include sodium carbonate,potassium carbonate, and cesium carbonate.

Compounds of formula (3) where R² is hydrogen can be converted tocompounds of formula (3) where R² is nitro by treatment with nitric acidin the presence of sulfuric acid. Compounds of formula (3) where R² isnitro can be converted to compounds of formula (4) where R² is nitro bythe methods described above.

Scheme 2 shows the synthesis of compounds of formula (5). Compounds offormula (4) can be treated with an isocyanate or thioisocyanate in thepresence of a base such as N-methylmorpholine or triethylamine toprovide compounds of formula (5) where X is N(R^(a))C(S)N(R^(b)) orN(R^(a))C(O)N(R^(b)).

Alternatively, compounds of formula (4) can be coupled to anappropriately substituted carboxylic acid under standard couplingconditions to provide compounds of formula (5) where X is N(R^(a))C(O).Standard coupling conditions include a coupling agent such as EDCI orDCC, a base such as N-methylmorpholine or triethylamine, and optionallyHOBT.

Compounds of formula (5) where R² is nitro can be converted to compoundsof formula (5) where R² is NH₂ by reduction under conditions known tothose of ordinary skill in the art (e.g., treatment with 10% Pd/C).Compounds of formula (5) where R² is NH₂ can be further functionalizedthrough reaction with an alkylating or acylating agent in the presenceof a base.

As shown in Scheme 3, compounds of formula (3) where X′ is Br or I canbe coupled with an appropriately substituted organometallic couplingpartner (M-A-X-R⁵, where M is a metal such as a boronic acid, a boronicester, or an alkylstannane) under the conditions described in Scheme 1to provide compounds of formula (5).

The synthesis of compounds of formula (5) is shown in Scheme 4.Compounds of formula (6) (R^(a) is an alkyl group) can be converted tocompounds of formula (5) by treatment with an appropriately substitutedhalide (X′-A-X-R⁵, where X′ is Br or I) under the conditions describedin Scheme 1.

An alternative synthesis of compounds of formula (5) is shown in Scheme5. Compounds of formula (6) can be coupled to an appropriatelysubstituted halide (X′-A-NH₂, where X′ is Br or I) using the conditionsdescribed in Scheme 1 to provide compounds of formula (7) which can beconverted to compounds of formula (5) using the conditions described inScheme 2.

As shown in Scheme 6, compounds of formula (3) can be converted tocompounds of formula (8), where R¹ is an alkyl group, by treatment withan alkylating agent in the presence of a base such as triethylamine ordiisopropylethylamine. Compounds of formula (8) can be converted tocompounds of formula (9) (where R¹ is alkyl) by the methods previouslydescribed.

The methods described above can also be used to prepared compounds offormula (I) where R³ is hydrogen and R⁴ is A-X-R⁵ by substituting theappropriate starting materials.

The present invention will now be described in connection with certainpreferred embodiments which are not intended to limit its scope. On thecontrary, the present invention covers all alternatives, modifications,and equivalents as can be included within the scope of the claims. Thus,the following examples, which include preferred embodiments, willillustrate the preferred practice of the present invention, it beingunderstood that the examples are for the purposes of illustration ofcertain preferred embodiments and are presented to provide what isbelieved to be the most useful and readily understood description of itsprocedures and conceptual aspects.

Compounds of the invention were named by ACD/ChemSketch version 5.0(developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada).

EXAMPLE 1N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]ureaEXAMPLE 1A Methyl 3-bromo-2-methylbenzoate

A suspension of 3-bromo-2-methylbenzoic acid (9.9 g,46 mmol) in thionylchloride (20 mL) was heated to 60° C. for 1 hour, cooled to roomtemperature, and concentrated. The residue was suspended in 50 mL ofmethanol, cooled to 0° C., treated slowly with triethylamine (12.7 μL,92 mmol), warmed to room temperature, and concentrated. The residue waspartitioned between ethyl acetate and water and the organic phase waswashed with saturated NaHCO₃ and brine, dried (MgSO₄), filtered, andconcentrated to give 7.39 g of the desired product. R_(f)=0.5 (10% ethylacetate/hexanes).

EXAMPLE 1B Methyl 3-bromo-2-(bromomethyl)benzoate

A suspension of Example 1A (7.4 g, 32.3 mmol), NBS (6.9 g, 38.8 mmol),and benzoyl peroxide (0.782 g, 3.2 mmol) in benzene (100 mL) was stirredat reflux for 5 hours, cooled to 0° C., and filtered. The solid waswashed with diethyl ether and the filtrate was washed sequentially with10% Na₂S₂O₃ (2×20 mL), and brine, dried (MgSO₄), filtered, andconcentrated. The residue was purified by silica gel chromatography with5 to 10% ethyl acetate/hexanes to give 9.32 g of the desired product.R_(f)=0.2 (5% ethyl acetate/hexanes).

EXAMPLE 1C 4-bromo-1-isoindolinone

A solution of Example 1B (8.3 g, 26.9 mmol) in THF (100 mL) was treateddropwise with concentrated NH₄OH (9 mL, 135 mmol) stirred at roomtemperature for 2 days, diluted with 30 mL water, cooled to 0° C., andfiltered. The filter cake was washed with water and ethyl acetate anddried to give 3.34 g of the desired product. MS (ESI(+)) m/e 212 (M+H)⁺.

EXAMPLE 1D 4-(4-aminophenyl)-1-isoindolinone

A suspension of Example 1C (2 g, 9.43 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)aniline (2.5 g, 11.3mmol), and Na₂CO₃ (2.2 g, 20.8 mmol) in DME (68 mL) and water (17 mL)was purged with nitrogen, treated with Pd(PPh₃)₄ (1 g, 0.9 mmol), andstirred at 90° C. for 19 hours. The reaction mixture was cooled to roomtemperature, concentrated to one-third its original volume, diluted withethyl acetate (30 mL) and water (20 mL), and filtered. The filter cakewas washed with water and ethyl acetate and dried to give 1.25 g of thedesired product. MS (ESI(+)) m/e 225 (M+H)⁺.

EXAMPLE 1EN-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

An 0° C. suspension of Example 1D (1.94 g, 8.68 mmol) in THF (44 mL) wassequentially treated dropwise with N-methylmorpholine (0.95 mL, 8.68mmol) and 3-methylphenyl isocyanate (1.12 mL, 8.68 mmol). The mixturewas stirred for 1 hour, diluted with THF (20 mL), stirred at roomtemperature for 3 hours, and quenched with water (20 mL). The organicphase was washed with brine, dried (MgSO₄), filtered, and concentrated.The residue was suspended in 5% methanol/dichloromethane and filtered.The filter cake was washed with dichloromethane and dried to provide2.94 g of the desired product. 1H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H),4.52 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.23–7.27(m, 1H), 7.31 (s, 1H), 7.53–7.60 (m, 5H), 7.64–7.67 (m, 2H), 8.63 (s,1H), 8.65 (s, 1H), 8.80 (s, 1H); MS (ESI(+)) m/e 358.1 (M+H)⁺.

EXAMPLE 2N-(3-methylphenyl)-N′-[4-(7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]ureaEXAMPLE 2A 4-bromo-7-nitro-1-isoindolinone

A 0° C. solution of Example 1C (5 g, 23.6 mmol) in 10 mL sulfuric acidwas treated with a solution of concentrated nitric acid (1.55 mL, 24.7mmol) in 10 mL sulfuric acid via addition funnel. The resulting mixturewas stirred at 0° C. for 1 hour, warmed to room temperature, stirredovernight, poured over ice, and filtered. The filter cake was washedwith water and diethyl ether and then dried to give 5.39 g of thedesired product. ¹H NMR (300 MHz, DMSO-d₆) δ 4.39 (s, 2H); 7.88 (d,J=8.1 Hz, 1H); 8.05 (d, J=8.5 Hz, 1H); 9.17 (s, 1H).

EXAMPLE 2BN-(3-methylphenyl)-N′-[4-(7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 2A for Example1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 4.59 (s, 2H); 6.81 (d,J=7.5 Hz, 1H); 7.17 (t, J=7.6 Hz, 1H); 7.25 (d, J=8.8 Hz, 1H); 7.31 (brs, 1H); 7.61 (apparent s, 4H); 7.80 (d, J=8.1 Hz, 1H); 7.94 (d, J=8.1Hz, 1H); 8.67 (s, 1H); 8.89 (s, 1H); 9.05 (s, 1H); MS (ESI(+)) m/e 403(M+H)⁺.

EXAMPLE 3N-[4-(7-amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

A mixture of Example 2 (1.29 g, 3.21 mmol) and 10% Pd on carbon (100 mg)in DMF (10 mL) under a hydrogen atmosphere was stirred at roomtemperature overnight. The mixture was filtered through diatomaceousearth (Celite®) and the pad was washed with methanol. The filtrate wasconcentrated, diluted with water, cooled to 0° C., and filtered. Thefilter cake was washed with water and diethyl ether then dried to give0.88 g of the desired product. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H);4.40 (s, 2H); 6.17 (s, 2H); 6.66 (d, J=8.5 Hz, 1H); 6.79 (d, J=7.1 Hz,1H); 7.16 (t, J=7.6 Hz, 1H); 7.24 (d, J=8.5 Hz, 1H); 7.30–7.35 (m, 2H);7.39 (d, J=8.8 Hz, 2H); 7.44 (d, J=8.8 Hz, 2H); 8.25 (s, 1H); 8.58 (s,1H); 8.68 (s, 1H); MS (ESI(−)) m/e 371 (M−H)⁻.

EXAMPLE 4N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetamide

A suspension of Example 3 (0.088 g, 0.24 mmol) in THF (2 mL) was treateddropwise via syringe with acetyl chloride (0.017 mL, 0.24 mmol), stirredat room temperature overnight, quenched with water, cooled to 0° C., andfiltered. The filter cake was dried to give 77 mg of the desiredproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.17 (s, 3H); 2.28 (s, 3H); 4.55(s, 2H); 6.80 (d, J=7.1 Hz, 1H); 7.16 (t, J=7.8 Hz, 1H); 7.24 (d, J=8.1Hz, 1H); 7.31 (br s, 1H); 7.50 (d, J=8.8 Hz, 2H); 7.56 (d, J=8.8 Hz,2H); 7.61 (d, J=8.5 Hz, 1H); 8.38 (d, J=8.1 Hz, 1H); 8.62 (s, 1H); 8.78(s, 1H); 8.96 (s, 1H); 10.58 (s, 1H); MS (ESI(+)) m/e 415 (M+H)⁺.

EXAMPLE 5N-(2-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2-methylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 2.26 (s, 3H); 4.51 (s, 2H); 6.97 (t, J=7.5 Hz, 1H); 7.1–7.2(m, 2H); 7.5–7.7 (m, 7H); 7.83 (d, J=7.5 Hz, 1H); 7.96 (s, 1H); 8.63 (s,1H); 9.15 (s, 1H); MS (ESI(+)) m/e 358 (M+H)⁺.

EXAMPLE 6N-(4-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 4-methylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 2.25 (s, 3H); 4.51 (s, 2H); 7.09 (d, J=8.4 Hz, 1H); 7.35 (d,J=8.4 Hz, 2H); 7.5–7.7 (m, 7H); 8.58 (s, 1H); 8.63 (s, 1H); 8.76 (s,1H); MS (ESI(+)) m/e 358 (M+H)⁺.

EXAMPLE 7N-(2-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2-methoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 3.89 (s, 3H); 4.51 (s, 2H); 6.91 (td, J=7.6, 1.3 Hz, 1H);6.96 (td, J=7.6, 1.7 Hz, 1H); 7.03 (dd, J=8.1, 1.3 Hz, 1H); 7.5–7.7 (m,7H); 8.15 (dd, J=8.0, 1.7 Hz, 1H); 8.26 (s, 1H); 8.63 (s, 1H); 9.45 (s,1H); MS (ESI(+)) m/e 374 (M+H)⁺.

EXAMPLE 8N-(3-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-methoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 3.74 (s, 3H); 4.51 (s, 2H); 6.57 (dd, J=8.1, 1.9 Hz, 1H);6.95 (d, J=8.1 Hz, 1H); 7.15–7.20 (m, 2H); 7.5–7.7 (m, 7H); 8.63 (s,1H); 8.71 (s, 1H); 8.79 (s, 1H); MS (ESI(+)) m/e 374 (M+H)⁺.

EXAMPLE 9N-(4-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 4-methoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 3.72 (s, 3H); 4.51 (s, 2H); 6.88 (d, J=8.7 Hz, 2H); 7.37 (d,J=8.7 Hz, 2H); 7.5–7.7 (m, 7H); 8.50 (s, 1H); 8.62 (s, 1H); 8.72 (s,1H); MS (ESI(+)) m/e 374 (M+H)⁺.

EXAMPLE 10N-(2-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2-fluorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.52 (m, 2H); 7.95–7.05 (m, 1H); 7.15 (t, J=7.6 Hz, 1H);7.1–7.2 (m, 1H); 7.5–7.7 (m, 7H); 8.16 (d, J=8.4 Hz, 1H); 8.58 (m, 1H);8.63 (s, 1H); 9.21 (s, 1H); MS (ESI(+)) m/e 362 (M+H)⁺.

EXAMPLE 11N-(3-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-fluorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 6.79 (td, J=8.5, 2.0 Hz, 1H); 7.14 (dd, J=8.1,2.0 Hz, 1H); 7.31 (apparent q, J=8.1 Hz, 1H); 7.50 (dt, J=11.9, 2.2 Hz,1H); 7.55–7.60 (m, 5H); 7.6–7.7 (m, 2H); 8.63 (s, 1H); 8.88 (s, 1H);8.94 (s, 1H); MS (ESI(+)) m/e 362 (M+H)⁺.

EXAMPLE 12N-(4-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 4-fluorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 7.13 (t, J=8.9 Hz, 2H); 7.45–7.65 (m, 9H); 8.63(s, 1H); 8.74 (s, 1H); 8.81 (s, 1H); MS (ESI(+)) m/e 362 (M+H)⁺.

EXAMPLE 13N-(2-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2-chlorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.05 (d, J=8.7 Hz, 1H); 7.32 (d, J=8.7 Hz, 1H);7.47 (dd, J=8.1, 1.6 Hz, 1H); 7.5–7.7 (m, 7H); 8.18 (dd, J=8.3, 1.4 Hz,1H); 8.34 (s, 1H); 8.63 (s, 1H); 9.55 (s, 1H); MS (ESI(+)) m/e 378(M+H)⁺.

EXAMPLE 14N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-chlorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.0–7.1 (m, 1H); 7.25–7.35 (m, 2H); 7.5–7.8 (m,8H); 8.66 (s, 1H); 8.91 (s, 1H); 8.94 (s, 1H); MS (ESI(+)) m/e 378(M+H)⁺.

EXAMPLE 15N-(4-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 4-chlorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 7.30–7.35 (m, 2H); 7.48–7.53 (m, 2H); 7.53–7.60(m, 5H); 7.63–7.68 (m, 2H); 8.63 (s, 1H); 8.85 (s, 2H); MS (ESI(+)) m/e378 (M+H)⁺.

EXAMPLE 16N-(2-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2-bromophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.52 (s, 2H); 6.99 (d, J=7.5 Hz, 1H); 7.35 (d, J=8.4 Hz, 1H);7.5–7.7 (m, 8H); 8.08 (dd, J=8.3, 1.4 Hz, 1H); 8.17 (s, 1H); 8.63 (s,1H); 9.60 (s, 1H); MS (ESI(+)) m/e 422, 424 (M+H)⁺.

EXAMPLE 17N-(3-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-bromophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.1–7.2 (m, 1H); 7.25 (t, J=8.0 Hz, 1H);7.3–7.4 (m, 1H); 7.5–7.7 (m, 7H); 7.87 (t, J=1.9 Hz, 1H); 8.66 (s, 1H);8.91 (s, 1H); 8.92 (s, 1H); MS (ESI(+)) m/e 422, 424 (M+H)⁺.

EXAMPLE 18N-(4-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 4-bromophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 7.46 (apparent s, 4H); 7.3–7.6 (m, 5H);7.63–7.67 (m, 2H); 8.63 (s, 1H); 8.86 (s, 2H); MS (ESI(+)) m/e 422, 424(M+H)⁺.

EXAMPLE 19N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-(trifluoromethoxy)phenyl]urea

The desired product was prepared by substituting4-trifluoromethoxyphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (500 MHz, DMSO-d₆) δ 4.51 (s, 2H); 7.30 (d, J=8.7 Hz,2H); 7.5–7.6 (m, 7H); 7.6–7.7 (m, 2H); 8.63 (s, 1H); 8.87 (s, 1H); 8.92(s, 1H); MS (ESI(+)) m/e 428 (M+H)⁺.

EXAMPLE 20N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-phenoxyphenyl)urea

The desired product was prepared by substituting 3-phenoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.50 (s, 2H); 6.62 (dd, J=8.1, 1.6 Hz, 1H); 7.04 (d, J=7.5Hz, 2H); 7.16 (t, J=7.5 Hz, 2H); 7.25–7.30 (m, 2H); 7.41 (d, J=7.5 Hz,1H); 7.5–7.6 (m, 5H); 7.64 (t, J=7.0 Hz, 2H); 8.62 (s, 1H); 8.78 (s,1H); 8.83 (s, 1H); MS (ESI(+)) m/e 436 (M+H)⁺.

EXAMPLE 21N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting 4-trifluoromethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.5–7.7 (m, 11H); 8.66 (s, 1H); 8.96 (s, 1H);9.16 (s, 1H); MS (ESI(+)) m/e 412 (M+H)⁺.

EXAMPLE 22N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(4-phenoxyphenyl)urea

The desired product was prepared by substituting 4-phenoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 6.95–7.05 (m, 4H); 7.09 (t, J=7.3 Hz, 1H); 7.36(t, J=8.7 Hz, 2H); 7.45–7.50 (m, 2H); 7.52–7.60 (m, 5H); 7.62–7.70 (m,2H); 8.63 (s, 1H); 8.72 (s, 1H); 8.80 (s, 1H); MS (ESI(+)) m/e 436(M+H)⁺.

EXAMPLE 23N-[3-(benzyloxy)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-benzyloxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 5.09 (s, 2H); 6.65 (dd, J=8.1, 1.9 Hz, 1H);6.97 (dd, J=7.8, 1.3 Hz, 1H); 7.19 (t, J=8.1 Hz, 1H); 7.27 (t, J=2.2 Hz,1H); 7.33 (t, J=7.2 Hz, 1H); 7.40 (t, J=7.3 Hz, 2H); 7.46 (d, J=7.2 Hz,2H); 7.5–7.6 (m, 5H); 7.6–7.7 (m, 2H); 8.63 (s, 1H); 8.71 (s, 1H); 8.80(s, 1H); MS (ESI(+)) m/e 450 (M+H)⁺.

EXAMPLE 24N-(2,3-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,3-dimethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 2.15 (s, 3H); 2.26 (s, 3H); 4.51 (s, 2H); 6.91 (d, J=7.5 Hz,1H); 7.04 (t, J=7.8 Hz, 1H); 7.52–7.60 (m, 6H); 7.63–7.70 (m, 2H); 7.98(s, 1H); 8.62 (s, 1H); 9.05 (s, 1H); MS (ESI(+)) m/e 372 (M+H)⁺.

EXAMPLE 25N-(2,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,4-dimethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 2.22 (s, 3H); 2.24 (s, 3H); 4.51 (s, 2H); 6.9–7.0 (m, 2H);7.5–7.7 (m, 8H); 7.88 (s, 1H); 8.62 (s, 1H); 9.06 (s, 1H); MS (ESI(+))m/e 372 (M+H)⁺.

EXAMPLE 26N-(2,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,5-dimethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 2.21 (s, 3H); 2.26 (s, 3H); 4.51 (s, 2H); 6.78 (d, J=7.5 Hz,1H); 7.06 (d, J=7.5 Hz, 1H); 7.5–7.6 (m, 5H); 7.6–7.7 (m, 3H); 7.90 (s,1H); 8.63 (s, 1H); 9.13 (s, 1H); MS (ESI(+)) m/e 372 (M+H)⁺.

EXAMPLE 27N-(3,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3,4-dimethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 2.16 (s, 3H); 2.20 (s, 3H); 4.52 (s, 2H); 7.03 (d, J=8.1 Hz,1H); 7.1–7.3 (m, 2H); 7.5–7.7 (m, 7H); 8.52 (s, 1H); 8.65 (s, 1H); 8.75(s, 1H); MS (ESI(+)) m/e 372 (M+H)⁺.

EXAMPLE 28N-(2,3-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,3-dimethoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 3.78 (s, 3H); 3.81 (s, 3H); 4.51 (s, 2H); 6.69 (dd, J=8.4,1.3 Hz, 1H); 6.99 (t, J=8.3 Hz, 1H); 7.5–7.6 (m, 5H); 7.63–7.67 (m, 2H);7.82 (dd, J=8.4, 1.3 Hz, 1H) 8.39 (s, 1H); 8.63 (s, 1H); 9.47 (s, 1H);MS (ESI(+)) m/e 404 (M+H)⁺.

EXAMPLE 29N-(2,4-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,4-dimethoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 3.74 (s, 3H); 3.87 (s, 3H); 4.51 (s, 2H); 6.49 (dd, J=8.7,2.8 Hz, 1H); 6.63 (d, J=2.5 Hz, 1H); 7.52–7.59 (m, 5H); 7.62–7.70 (m,2H); 7.95 (d, J=8.7 Hz, 1H); 8.02 (s, 1H); 8.62 (s, 1H); 9.29 (s, 1H);MS (ESI(+)) m/e 404 (M+H)⁺.

EXAMPLE 30N-(2,5-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,5-dimethoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 3.70 (s, 3H); 3.84 (s, 3H); 4.51 (s, 2H); 6.51 (dd, J=8.7,3.1 Hz, 1H); 6.94 (d, J=8.7 Hz, 1H); 7.53–7.60 (m, 5H); 7.63–7.67 (m,2H); 7.87 (d, J=2.8 Hz, 1H); 8.28 (s, 1H); 8.63 (s, 1H); 9.49 (s, 1H);MS (ESI(+)) m/e 404 (M+H)⁺.

EXAMPLE 31N-(3,4-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3,4-dimethoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 3.72 (s, 3H); 3.75 (s, 3H); 4.51 (s, 2H); 6.85–6.95 (m, 2H);7.22 (d, J=1.9 Hz, 1H); 7.5–7.6 (m, 5H); 7.62–7.66 (m, 2H); 8.54 (s,1H); 8.63 (s, 1H); 8.72 (s, 1H); MS (ESI(+)) m/e 404 (M+H)⁺.

EXAMPLE 32N-(3,5-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3,5-dimethoxyphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 6.15 (s, 1H); 6.70 (d, J=2.5 Hz, 2H); 7.53–7.60(m, 5H); 7.63–7.66 (m, 2H); 8.63 (s, 1H); 8.70 (s, 1H); 8.77 (s, 1H); MS(ESI(+)) m/e 404 (M+H)⁺.

EXAMPLE 33N-2,3-dihydro-1H-inden-5-yl-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 5-isocyanatoindane for3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ1.9–2.1 (m, 2H); 2.7–2.9 (m, 4H); 4.52 (s, 2H); 7.1–7.2 (m, 2H); 7.40(s, 1H); 7.5–7.7 (m, 7H); 8.58 (s, 1H); 8.67 (s, 1H); 8.77 (s, 1H); MS(ESI(+)) m/e 384 (M+H)⁺.

EXAMPLE 34N-1,3-benzodioxol-5-yl-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting5-isocyanato-1,3-benzodioxole for 3-methylphenyl isocyanate in Example1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.52 (s, 2H); 5.98 (s, 2H); 6.75–6.90(m, 2H); 7.22 (d, J=2.0 Hz, 1H); 7.5–7.7 (m, 7H); 8.61 (s, 1H); 8.67 (s,1H); 8.77 (s, 1H); MS (ESI(+)) m/e 388 (M+H)⁺.

EXAMPLE 35N-(2,3-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,3-dichlorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 7.28–7.36 (m, 2H); 7.55–7.62 (m, 5H); 7.64–7.67(m, 2H); 8.18 (dd, J=8.27, 1.40 Hz, 1H); 8.51 (s, 1H); 8.63 (s, 1H);9.61 (s, 1H); MS (ESI(+)) m/e 412 (M+H)⁺.

EXAMPLE 36N-(2,5-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 2,5-dichlorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.11 (dd, J=8.7, 2.5 Hz, 1H); 7.51 (d, J=8.7Hz, 1H); 7.55–7.62 (m, 5H); 7.63–7.68 (m, 2H); 8.34 (d, J=2.5 Hz, 1H);8.50 (s, 1H); 8.63 (s, 1H); 9.66 (s, 1H); MS (ESI(+)) m/e 412 (M+H)⁺.

EXAMPLE 37N-(3,4-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3,4-dichlorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 7.36 (dd, J=8.7, 2.5 Hz, 1H); 7.5–7.6 (m, 6H);7.63–7.68 (m, 2H); 7.89 (d, J=2.5 Hz, 1H); 8.63 (s, 1H); 8.95 (s, 1H);9.04 (s, 1H); MS (ESI(+)) m/e 412 (M+H)⁺.

EXAMPLE 38N-(3,5-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3,5-dichlorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (500 MHz,DMSO-d₆) δ 4.51 (s, 2H); 7.17 (s, 1H); 7.55–7.60 (m, 7H); 7.63–7.70 (m,2H); 8.63 (s, 1H); 9.03 (s, 1H); 9.10 (s, 1H); MS (ESI(+)) m/e 412(M+H)⁺.

EXAMPLE 39N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting4-chloro-3-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.52 (s, 2H);7.5–7.7 (m, 9H); 8.13 (d, J=2.0 Hz, 1H); 8.68 (s, 1H); 9.02 (s, 1H);9.23 (s, 1H); (ESI(−)) m/e 444 (M−H)⁻.

EXAMPLE 40N-(3-chloro-4-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting3-chloro-4-methoxyphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 3.79 (s, 3H); 4.50 (s, 2H); 7.08(d, J=9.2 Hz, 1H); 7.27 (dd, J=9.0, 3.0 Hz, 1H); 7.59 (m, 8H); 8.64 (s,1H); 8.67 (s, 1H); 8.81 (s, 1H); MS (ESI(+)) m/e 408 (M+H)⁺.

EXAMPLE 41N-(4-bromo-3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 4-bromo-3-methylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 2.32 (s, 3H); 4.52 (s, 2H); 7.27 (dd, J=8.82, 2.71 Hz, 1H);7.4–7.7 (m, 9H); 8.67 (s, 1H); 8.80 (s, 1H); 8.87 (s, 1H); MS (ESI(+))m/e 436 (M+H)⁺.

EXAMPLE 42N-(3-chloro-4-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-chloro-4-fluorophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.3–7.4 (m, 2H); 7.5–7.7 (m, 7H); 7.8–7.9 (m,1H); 8.66 (s, 1H); 8.92 (s, 1H); 8.93 (s, 1H); MS (ESI(+)) m/e 396(M+H)⁺.

EXAMPLE 43N-(3-chloro-4-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-chloro-4-methylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 2.27 (s, 3H); 4.52 (s, 2H); 7.2–7.3 (m, 2H); 7.5–7.8 (m, 8H);8.66 (s, 1H); 8.81 (s, 1H); 8.86 (s, 1H); MS (ESI(+)) m/e 392 (M+H)⁺.

EXAMPLE 44N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting 3-trifluoromethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 4.52 (s, 1H); 7.33 (d, J=7.5 Hz, 1H); 7.5–7.7 (m, 9H); 8.04(s, 1H); 8.66 (s, 1H); 8.95 (s, 1H); 9.10 (s, 1H); MS (ESI(+)) m/e 412(M+H)⁺.

EXAMPLE 45N-(3-ethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-ethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 1.19 (t, J=7.6 Hz, 3H); 2.58 (q, J=7.57 Hz, 2H); 4.52 (s,2H); 6.84 (d, J=7.5 Hz, 1H); 7.19 (t, J=7.8 Hz, 1H); 7.27 (d, J=8.5 Hz,1H); 7.34 (s, 1H); 7.61 (m, 7H); 8.65 (s, 2H); 8.79 (s, 1H); MS (ESI(+))m/e 372 (M+H)⁺.

EXAMPLE 46N-(3-cyanophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-cyanophenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.4–7.8 (m, 10H); 7.99 (s, 1H); 8.66 (s, 1H);9.00 (s, 1H); 9.08 (s, 1H); MS (ESI(+)) m/e 369 (M+H)⁺.

EXAMPLE 47 Methyl3-[({[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]amino}carbonyl)amino]benzoate

The desired product was prepared by substituting methyl3-isocyanatobenzoate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR(300 MHz, DMSO-d₆) δ 3.87 (s, 3H); 4.52 (s, 2H); 7.44 (t, J=7.8 Hz, 1H);7.5–7.7 (m, 9H); 8.22 (t, J=1.0 Hz, 1H); 8.66 (s, 1H); 8.87 (s, 1H);9.00 (s, 1H); MS (ESI(+)) m/e 419 (M+H)⁺.

EXAMPLE 48N-(3-acetylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-acetylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 2.58 (s, 3H); 4.52 (s, 2H); 7.45 (t, J=7.8 Hz, 1H); 7.5–7.7(m, 9H); 8.09 (t, J=2.0 Hz, 1H); 8.66 (s, 1H); 8.88 (s, 1H); 8.96 (s,1H); MS (ESI(+)) m/e 386 (M+H)⁺.

EXAMPLE 49N-[2-fluoro-5-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting2-fluoro-5-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.52 (s, 2H);7.3–7.7 (m, 9H); 8.6–8.7 (m, 2H); 8.94 (d, J=2.7 Hz, 1H); 9.32 (s, 1H);MS (ESI(+)) m/e 430 (M+H)⁺.

EXAMPLE 50N²,N²-dimethyl-N′-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}glycinamide

The desired product was prepared by substituting N,N-dimethylglycylchloride for acetyl chloride in Example 4. ¹H NMR (300 MHz, DMSO-d₆) δ2.28 (s, 3H); 2.87 (br s, 6H); 4.35 (br s, 2H); 4.59 (s, 2H); 6.80 (d,J=6.8 Hz, 1H); 7.16 (t, J=7.8 Hz, 1H); 7.25 (d, J=8.1 Hz, 1H); 7.31 (brs, 1H); 7.53 (d, J=8.8 Hz, 1H); 7.58 (d, J=8.8 Hz, 1H); 7.69 (d, J=8.5Hz, 1H); 8.31 (d, J=8.5 Hz, 1H); 8.68 (s, 1H); 8.86 (s, 1H); 9.05 (s,1H); 9.89 (br s, 1H); 10.87 (br s, 1H); MS (ESI(+)) m/e 458 (M+H)⁺.

EXAMPLE 51N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}nicotinamide

The desired product was prepared by substituting nicotinoyl chloride foracetyl chloride in Example 4. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H);4.63 (s, 2H); 6.80 (d, J=7.8 Hz, 1H); 7.17 (t, J=7.6 Hz, 1H); 7.25 (d,J=8.5 Hz, 1H); 7.31 (br s, 1H); 7.5–7.6 (m, 4H); 7.67 (dd, J=7.8, 4.8Hz, 1H); 7.73 (d, J=8.1 Hz, 1H); 8.32 (dt, J=8.1, 1.7 Hz, 1H); 8.53 (d,J=8.5 Hz, 1H); 8.63 (s, 1H); 8.80 (s, 1H); 8.84 (dd, J=4.8, 1.4 Hz, 1H);9.1–9.2 (m, 2H); 11.78 (s, 1H); MS (ESI(+)) m/e 478 (M+H)⁺.

EXAMPLE 52N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-phenylacetamide

The desired product was prepared by substituting phenylacetyl chloridefor acetyl chloride in Example 4. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s,3H); 3.79 (s, 2H); 4.53 (s, 2H); 6.80 (d, J=7.1 Hz, 1H); 7.1–7.6 (m,15H); 8.37 (d, J=8.5 Hz, 2H); 8.62 (s, 1H); 8.78 (s, 1H); 8.89 (s, 1H);10.71 (s, 1H); MS (ESI(−)) m/e 489 (M−H)⁻.

EXAMPLE 532-(2-methoxyethoxy)-N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetamide

The desired product was prepared by substituting (2-methoxyethoxy)acetylchloride for acetyl chloride in Example 4. ¹H NMR (300 MHz, DMSO-d₆) δ2.28 (s, 3H); 3.40–3.45 (m, 2H); 3.50–3.55 (m, 2H); 4.15 (s, 2H); 4.56(s, 2H); 6.80 (d, J=7.5 Hz, 1H); 7.16 (t, J=7.8 Hz, 1H); 7.24 (d, J=8.5Hz, 1H); 7.31 (br s, 1H); 7.51 (d, J=9.2 Hz, 2H); 7.56 (d, J=9.2 Hz,1H); 7.63 (d, J=8.5 Hz, 1H); 8.49 (d, J=8.5 Hz, 1H); 8.62 (s, 1H); 8.78(s, 1H); 8.89 (s, 1H); 11.35 (s, 1H); MS (ESI(+)) m/e 489 (M+H)⁺.

EXAMPLE 54N-(3-methylphenyl)-N′-[6-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-pyridinyl]ureaEXAMPLE 54A4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-isoindolinone

A suspension of Example 1C (10.6 g, 50 mmol) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (15.23 g,60 mmol) in DMF (390 mL) was stirred until a clear yellow solution wasobtained. The solution was then treated with potassium acetate (14.72 g,150 mmol), degassed with nitrogen, treated with[1.1′-bis(diphenylphosphino)-ferrocene]dichloropalladium [II].CH₂Cl₂ (7g, 8.5 mmol) and heated to 90° C. overnight. The reaction was cooled toroom temperature and filtered through diatomaceous earth (Celite®), andconcentrated. The concentrate was partitioned between water and ethylacetate and filtered through diatomaceous earth (Celite®). The organicphase was dried (Na₂SO₄), filtered, and concentrated. The crude productwas purified by silica gel chromatography eluting with 100% ethylacetate and triturated from hexanes to give 4.56 g (35% yield) of thedesired product. m.p.: 189–191° C.

EXAMPLE 54BN-(3-methylphenyl)-N′-[6-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-pyridinyl]urea

A solution of Example 54A (259 mg, 1 mmol) andN-(6-bromo-3-pyridinyl)-N′-(3-methylphenyl)urea (367 mg, 1.2 mmol)(prepared from 2-amino-4-bromopyridine and m-tolylisocyanate followingthe procedure of Example 1E) in toluene (6 mL) and ethanol (6 mL) wasdegassed with N₂ then treated sequentially with a solution of Na₂CO₃(509 mg, 4.8 mmol) in water (3 mL) andtetrakis(triphenylphosphine)palladium (0) (208 mg, 0.187 mmol) andstirred at reflux overnight. The resulting suspension was cooled to roomtemperature, diluted with diethyl ether, and filtered. The filter cakewas washed with water, diethyl ether, dichloromethane, ethyl acetate,and methanol. The combined filtrates were concentrated to give 51 mg ofthe desired product. ¹H NMR (300 MHz, DMSO-d₆) δ 10.35 (s,1H), 9.58(s,1H), 8.73 (s, 1H), 8.56 (s,1H), 8.06 (d, J=6 Hz, 1H), 7.56–7.81 (m,4H), 7.3–7.46 (m, 2H), 7.20 (t, J=6 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 4.56(s, 2H), 2.31 (s,3H); MS (ESI(+)) m/e 359 (M+H)⁺.

EXAMPLE 55 4-(4-phenoxyphenyl)-1-isoindolinone EXAMPLE 55A4-iodo-1-isoindolinone

The desired product was prepared by substituting 3-iodo-2-methylbenzoicacid for 3-bromo-2-methylbenzoic acid in Examples 1A,1B, and 1C. MS(DCI(+)) m/e 277 (M+NH₄)⁺.

EXAMPLE 55B 4-(4-phenoxyphenyl)-1-isoindolinone

A suspension of Example 55A (301 mg, 1.16 mmol), 4-phenoxyphenylboronicacid (271 mg, 1.27 mmol) and Na₂CO₃ (403 mg, 4.75 mmol) in DME (10 mL),water (4.8 mL), and ethanol (2.4 mL) was degassed with N₂ for 45minutes, treated with Pd(PPh₃)₄ (120 mg), and heated to 80° C.overnight. The suspension was cooled to room temperature, poured intowater, and extracted with ethyl acetate. The combined extracts weredried (Na₂SO₄), filtered, and concentrated. The concentrate wastriturated with warm ethanol to give 183 mg of the desired product. ¹HNMR (300 MHz, DMSO-d₆) δ 4.51 (s, 2H); 7.07–7.13 (m, 3H); 7.20 (t, J=7.5Hz, 1H); 7.33 (t, J=7.1 Hz, 1H); 7.38–7.47 (m, 3H); 7.59 (t, J=7.5 Hz,1H); 7.62–7.69 (m, 3H); 8.69 (s, 1H); MS (ESI(+)) m/e 302.1 (M+H)⁺.

EXAMPLE 564-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]-3-fluorophenyl}-1-isoindolinone

The desired product was prepared by substitutingN-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-aminefor 4-phenoxyphenylboronic acid in Example 55B. ¹H NMR (300 MHz,DMSO-d₆) δ 2.34 (s, 3H); 2.40 (s, 3H); 4.58 (s, 2H); 6.80 (s, 1H); 7.10(s, 1H); 7.53 (dd, J=8.5, 1.7 Hz, 1H); 7.58–7.63 (m, 2H); 7.69 (d, J=2.4Hz, 1H); 7.72 (dd, J=3.4, 1.0 Hz, 1H); 8.43 (t, J=8.5 Hz, 1H); 8.72 (s,1H); 10.54 (s, 1H); MS (ESI(+)) m/e 388.1 (M+H)⁺.

EXAMPLE 57N-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N-(3-methylphenyl)ureaEXAMPLE 57A 4-(4-amino-3-fluorophenyl)-1-isoindolinone

The desired product was prepared by substituting Example 54A and4-bromo-2-fluoroaniline for 4-phenoxyphenylboronic acid and Example 55A,respectively, in Example 55B. MS (ESI(+)) m/e 241 (M+H)⁺.

EXAMPLE 57BN-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 57A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 4.55 (s,2H); 6.82 (d, J=7.8 Hz, 1H); 7.18 (t, J=7.6 Hz, 1H); 7.24–7.26 (m, 1H);7.31 (s, 1H); 7.42 (dd, J=9.0, 1.5 Hz, 1H); 7.54–7.61 (m, 2H); 7.67–7.69(m, 2H); 8.29 (t, J=8.7 Hz, 1H); 8.68 (m, J=5.1 Hz, 2H); 9.04 (s, 1H);MS (ESI(+)) m/e 376.1 (M+H)⁺.

EXAMPLE 58N-(3-chlorophenyl)-N-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 57A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.55 (s, 2H); 7.06 (ddd, J=7.7,2.0, 1.2 Hz, 1H); 7.26 (m, 1H); 7.33 (t, J=8.0 Hz, 1H); 7.43 (dd, J=8.5,1.7 Hz, 1H); 7.55–7.61 (m, 2H); 7.70–7.67 (m, 2H); 7.75 (t, J=2.0 Hz,1H); 8.25 (t, J=8.5 Hz, 1H); 8.68 (s, 1H); 8.75 (d, J=2.4 Hz, 1H); 9.30(s, 1H); MS (ESI(+)) m/e 396.0 (M+H)⁺.

EXAMPLE 59N-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 57A for Example1D and 3-trifluoromethyl-4-fluorophenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.55 (s, 2H);7.42–7.50 (m, 2H); 7.56–7.67 (m, 3H); 7.68–7.70 (m, 2H); 8.03 (dd,J=6.4, 2.7 Hz, 1H); 8.23 (t, J=8.5 Hz, 1H); 8.69 (s, 1H); 8.77 (d, J=2.0Hz, 1H); 9.44 (s, 1H); MS (ESI(+)) m/e 448.1 (M+H)⁺.

EXAMPLE 60N-(4-chlorophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 57A for Example1D and 4-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.55 (s, 2H); 7.36 (d, J=8.8 Hz,2H); 7.43 (dd, J=8.7, 1.5 Hz, 1H); 7.51 (d, J=8.8 Hz, 2H); 7.55–7.61 (m,2H); 7.67–7.70 (m, 2H); 8.26 (t, J=8.7 Hz, 1H); 8.68 (s, 1H); 8.71 (d,J=2.4 Hz, 1H); 9.24 (s, 1H); MS (ESI(+)) m/e 396.0 (M+H)⁺.

EXAMPLE 61N-(3-bromophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 57A for Example1D and 3-bromophenyl isocyanate for 3-methylphenyl isocyanate in Example1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.55 (s, 2H); 7.19 (dt, J=7.0, 2.1 Hz,1H); 7.24–7.30 (m, 2H); 7.43 (dd, J=8.5, 1.7 Hz, 1H); 7.55–7.61 (m, 2H);7.67–7.70 (m, 2H); 7.89 (s, 1H); 8.25 (t, J=8.5 Hz, 1H); 8.69 (s, 1H);8.74 (d, J=2.4 Hz, 1H); 9.29 (s, 1H); MS (ESI(+)) m/e 439.9, 441.9(M+H)⁺.

EXAMPLE 62N-(3,4-dimethylphenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 57A for Example1D and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.17 (s, 3H); 2.20 (s, 3H); 4.55(s, 2H); 7.05 (d, J=8.1 Hz, 1H); 7.19 (dd, J=8.1, 2.4 Hz, 1H); 7.24(d,J=2.0 Hz, 1H); 7.41 (dd,J=8.5, 1.4 Hz, 1H); 7.53–7.61 (m, 2H);7.67–7.69 (m, 2H); 8.29 (t, J=8.6 Hz, 1H); 8.63 (d, J=2.7 Hz, 1H); 8.68(s, 1H); 8.94 (s, 1H); MS (ESI(+)) m/e 390.1 (M+H)⁺.

EXAMPLE 63N-(3-methylphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethoxy)phenyl]ureaEXAMPLE 63A 4-[4-amino-3-(trifluoromethoxy)phenyl]-1-isoindolinone

The desired product was prepared by substituting Example 54A and2-trifluoromethoxy-4-bromoaniline for 4-phenoxyphenylboronic acid andExample 55A, respectively in Example 55B. MS (ESI(+)) m/e 309 (M+H)⁺.

EXAMPLE 63BN-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethoxy)phenyl]urea

The desired product was prepared by substituting Example 63A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H); 4.54 (s,2H); 6.84 (d, J=7.1 Hz, 1H); 7.19 (t, J=7.8 Hz, 1H); 7.25–7.28 (m, 1H);7.33 (s, 1H); 7.58–7.64 (m, 3H); 7.69–7.71 (m, 2H); 8.41 (d, J=8.8 Hz,1H); 8.59 (s, 1H); 8.68 (s, 1H); 9.26 (s, 1H); MS (ESI(+)) m/e 442.0(M+H)⁺.

EXAMPLE 64N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethoxy)phenyl]urea

The desired product was prepared by substituting Example 63A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.54 (s, 2H); 7.07 (ddd, J=7.8,2.0, 1.0 Hz, 1H); 7.27 (d, J=8.8 Hz, 1H); 7.35 (t, J=8.0 Hz, 1H);7.58–7.71 (m, 5H); 7.76 (t, J=2.0 Hz, 1H); 8.38 (d, J=9.2 Hz, 1H); 8.66(s, 1H); 8.68 (s, 1H); 9.51 (s, 1H); MS (ESI(+)) m/e 462.0 (M+H)⁺.

EXAMPLE 65N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3,5-dimethylphenylisocyanate for 3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz,DMSO-d₆) δ 2.24 (s, 6H); 4.52 (s, 2H); 6.63 (s, 1H); 7.09 (s, 2H);7.52–7.59 (m, 5H); 7.64–7.67 (m, 2H); 8.55 (s, 1H); 8.65 (s, 1H); 8.78(s, 1H); MS (ESI(+)) m/e 372.1 (M+H)⁺.

EXAMPLE 66N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting phenyl isocyanate for3-methylphenyl isocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ4.52 (s, 2H); 6.98 (t, J=7.3 Hz, 1H); 7.29 (t, J=8.0 Hz, 2H); 7.47 (d,J=7.8 Hz, 2H); 7.53–7.60 (m, 5H); 7.64–7.67 (m, 2H); 8.65 (s, 1H); 8.71(s, 1H); 8.82 (s, 1H); MS (ESI(−)) m/e 342.1 (M−H)⁻.

EXAMPLE 67N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.52 (s, 2H); 7.45(app t, J=10.2 Hz, 1H); 7.54–7.61 (m, 5H); 7.64–7.69 (m, 3H); 8.02 (dd,J=6.4, 2.7 Hz, 1H); 8.66 (s, 1H); 8.97 (s, 1H); 9.09 (s, 1H); MS(ESI(+)) m/e 430.1 (M+H)⁺.

EXAMPLE 68N-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 68A 4-(4-Amino-3-methyl-phenyl-2,3-dihydro-isoindol-1-one

The desired product was prepared by substituting Example 54A and2-methyl-4-bromoaniline for 4-phenoxyphenylboronic acid and Example 55A,respectively, in Example 55B MS (ESI(+)) m/e 239 (M+H)⁺.

EXAMPLE 68BN-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-AP-(3-methylphenyl)urea

The desired product was prepared by substituting Example 68A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 2.32 (s,3H); 4.53 (s, 2H); 6.80 (d, J=7.1 Hz, 1H); 7.17 (t, J=7.8 Hz, 1H); 7.25(d, J=8.5 Hz, 1H); 7.33 (s, 1H); 7.42 (dd, J=8.5, 2.4 Hz, 1H); 7.45 (d,J=1.4 Hz, 1H); 7.57 (m, 1H); 7.65 (m, 2H); 8.02 (m, J=8.5 Hz, 2H); 8.67(s, 1H); 9.03 (s, 1H); MS (ESI(+)) m/e 372.1 (M+H)⁺.

EXAMPLE 69N-(3-chlorophenyl)-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 68A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (s, 3H); 4.53 (s, 2H);7.01–7.05 (m, 1H); 7.24–7.27 (m, 1H); 7.32 (t, J=8.0 Hz, 1H); 7.43 (dd,J=8.5, 2.4 Hz, 1H); 7.46 (s, 1H); 7.57 (t, J=7.5 Hz, 1H); 7.63–7.67 (m,2H); 7.77 (t, J=2.0 Hz, 1H); 7.97 (d, J=8.1 Hz, 1H); 8.11 (s, 1H); 8.68(s, 1H); 9.30 (s, 1H); MS (ESI(+)) m/e 392.0 (M+H)⁺.

EXAMPLE 70N-(3,4-dimethylphenyl)-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 68A for Example1D and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.16 (s, 3H); 2.20 (s, 3H); 2.32(s, 3H); 4.52 (s, 2H); 7.04 (d, J=8.1 Hz, 1H); 7.19 (dd, J=8.1, 1.7 Hz,1H); 7.25 (d, J=1.7 Hz, 1H); 7.40 (dd, J=8.1, 1.7 Hz, 1H); 7.44 (d,J=1.7 Hz, 1H); 7.54–7.59 (m, 1H); 7.63–7.66 (m, 2H); 7.96 (s, 1H); 8.02(d, J=8.5 Hz, 1H); 8.65 (s, 1H); 8.92 (s, 1H); MS (ESI(+)) m/e 386.1(M+H)⁺.

EXAMPLE 71N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 68A for Example1D and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (s, 3H); 4.52(s, 2H); 7.45 (m, 3H); 7.57 (m, 1H); 7.65 (m, 3H); 7.94 (d, J=8.1 Hz,1H); 8.04 (dd, J=6.4, 2.7 Hz, 1H); 8.13 (s, 1H); 8.66 (s, 1H); 9.42 (s,1H); MS (ESI(+)) m/e 444.1 (M+H)⁺.

EXAMPLE 72N-(5-methyl-3-pyridinyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]ureahydrochloride

A −5° C. solution of 5-methylnicotinohydrazide (353 mg, 2.33 mmol) inwater (2.3 mL) and concentrated HCl (2.75 mL) was treated dropwise witha solution of NaNO₂ (161 mg, 2.3 mmol) in water (2.3 mL), stirred at −5°C. for 30 minutes, adjusted to pH>7 with 10% aqueous K₂CO₃, andfiltered. The filter cake was dried under vacuum at room temperature toprovide the acyl azide. A portion of this intermediate (63 mg) intoluene (6 mL) was heated to reflux for 1 hour, cooled, and treated witha suspension of Example 1D (75 mg, 0.33 mmol) in dichloromethane (4 mL).The reaction was stirred at room temperature overnight and filtered. Thefilter cake was purified by silica gel chromatography with 6%methanol/dichloromethane. The purified product was stirred withsaturated NH₄Cl and filtered to give 53 mg of the desired product. ¹HNMR (300 MHz, DMSO-d₆) δ 2.41 (s, 3H); 4.52 (s, 2H); 7.55–7.68 (m, 7H);8.07 (s, 1H); 8.30 (s, 1H); 8.67 (s, 1H); 8.80 (s, 1H); 9.35 (s, 1H);9.52 (s, 1H); MS (ESI(+)) m/e 359.1 (M+H)⁺.

EXAMPLE 73N-(3,4-dimethylphenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]ureaEXAMPLE 73A 4-(4-amino-2-methylphenyl)-1-isoindolinone

The desired product was prepared by substituting Example 54A and3-methyl-4-bromoaniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 1C,respectively, in Example 1D. MS (ESI(+) m/e 239 (M+H)⁺.

EXAMPLE 73BN-(3,4-dimethylphenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 73A for Example1D and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.08 (s, 3H); 2.16 (s, 3H); 2.19(s, 3H); 4.13 (s, 2H); 7.03 (d, J=8.1 Hz, 1H); 7.17 (d, J=8.1 Hz, 2H);7.25 (d, J=2.0 Hz, 1H); 7.33 (dd, J=8.1, 2.4 Hz, 1H); 7.41–7.44 (m, 2H);7.54 (t, J=7.5 Hz, 1H); 7.67 (dd, J=7.5, 1.0 Hz, 1H); 8.49 (s, 1H); 8.56(s, 1H); 8.63 (s, 1H); MS (ESI(+)) m/e 386.1 (M+H)⁺.

EXAMPLE 74N-(3,5-dimethylphenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 73A for Example1D and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.08 (s, 3H); 2.24 (s, 6H); 4.14(s, 2H); 6.62 (s, 1H); 7.09 (s, 2H); 7.17 (d, J=8.1 Hz, 1H); 7.32 (dd,J=8.1, 2.0 Hz, 1H); 7.41–7.45 (m, 2H); 7.55 (t, J=7.5 Hz, 1H); 7.67 (dd,J=7.5, 1.0 Hz, 1H); 8.53 (s, 1H); 8.57 (s, 1H); 8.67 (s, 1H); MS(ESI(+)) m/e 386.1 (M+H)⁺.

EXAMPLE 75N-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 73A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.08 (s, 3H); 2.28 (s,3H); 4.13 (s, 2H); 6.79 (d, J=7.1 Hz, 1H); 7.16 (t, J=8.5 Hz, 2H);7.21–7.25 (m, 1H); 7.32–7.35 (m, 2H); 7.41–7.45 (m, 2H); 7.54 (t, J=7.5Hz, 1H); 7.67 (dd, J=7.5, 1.0 Hz, 1H); 8.56 (s, 1H); 8.61 (s, 1H); 8.68(s, 1H); MS (ESI(+)) m/e 372.1 (M+H)⁺.

EXAMPLE 76N-(3-chlorophenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 73A for Example1D and 3-chlorophenylisocyanate for 3-methylphenyl isocyanate in Example1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.09 (s, 3H); 4.13 (s, 2H); 7.02 (dt,J=6.9, 2.2 Hz, 1H); 7.19 (d, J=8.1 Hz, 1H); 7.26–7.36 (m, 3H); 7.41–7.45(m, 2H); 7.55 (t, J=7.5 Hz, 1H); 7.67 (dd, J=7.5, 1.0 Hz, 1H); 7.73–7.74(m, 1H); 8.56 (s, 1H); 8.84 (s, 1H); 8.97 (s, 1H); MS (ESI(+) m/e 392.1(M+H)⁺.

EXAMPLE 77N-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 73A for Example1D and 3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanatein Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.09 (s, 3H); 4.14 (s, 2H);7.20 (d, J=8.1 Hz, 1H); 7.30–7.37 (m, 2H); 7.43 (dd, J=7.5, 1.0 Hz, 1H);7.47 (d, J=2.0 Hz, 1H); 7.49–7.60 (m, 3H); 7.67 (dd, J=7.5, 1.0 Hz, 1H);8.04 (s, 1H); 8.56 (s, 1H); 8.83 (s, 1H); 9.08 (s, 1H); MS (ESI(+)) m/e426.1 (M+H)⁺.

EXAMPLE 78N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 73A for Example1D and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.09 (s, 3H); 4.13(s, 2H); 7.19 (d, J=8.1 Hz, 1H); 7.35 (dd, J=8.5, 2.0 Hz, 1H); 7.41–7.48(m, 3H); 7.55 (t, J=7.5 Hz, 1H); 7.63–7.68 (m, 2H); 8.03 (dd, J=6.8, 2.7Hz, 1H); 8.56 (s, 1H); 8.90 (s, 1H); 9.14 (s, 1H); MS (ESI(+)) m/e 444.1(M+H)⁺.

EXAMPLE 79N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 79A 4-(4-amino-3-chlorophenyl)-1-isoindolinone

The desired product was prepared by substituting Example 54A and2-chloro-4-bromoaniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 1C,respectively, in Example 1D. MS (ESI(+) m/e 259,261 (M+H)⁺.

EXAMPLE 79BN-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 79A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.30 (s, 3H); 4.54 (s,2H); 6.83 (d, J=6.8 Hz, 1H); 7.19 (t, J=7.6 Hz, 1H); 7.25–7.27 (m, 1H);7.33 (s, 1H); 7.56–7.61 (m, 2H); 7.67–7.70 (m, 2H); 7.73 (d, J=2.0 Hz,1H); 8.31 (d, J=8.8 Hz, 1H); 8.42 (s, 1H); 8.68 (s, 1H); 9.41 (s, 1H);MS (ESI(+)) m/e 392.0 (M+H)⁺.

EXAMPLE 80N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 79A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.54 (s, 2H); 7.06 (ddd, J=7.7,2.1, 1.0 Hz, 1H); 7.26 (ddd, J=8.2, 2.0, 1.0 Hz, 1H); 7.34 (t, J=8.1 Hz,1H); 7.57–7.61 (m, 2H); 7.67–7.70 (m, 2H); 7.74–7.77 (m, 2H); 8.28 (d,J=8.5 Hz, 1H); 8.49 (s, 1H); 8.68 (s, 1H); 9.67 (s, 1H); MS (ESI(+)) m/e412.0 (M+H)⁺.

EXAMPLE 81N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 79A for Example1D and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 6H); 4.54 (s, 2H); 6.66(s, 1H); 7.10 (s, 2H); 7.56–7.61 (m, 2H); 7.67–7.70 (m, 2H); 7.73 (d,J=2.0 Hz, 1H); 8.31 (d, J=8.8 Hz, 1H); 8.40 (s, 1H); 8.68 (s, 1H); 9.34(s, 1H); MS (ESI(+)) m/e 406.1 (M+H)⁺.

EXAMPLE 82N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 79A for Example1D and phenyl isocyanate for 3-methylphenyl isocyanate in Example 1E. ¹HNMR (300 MHz, DMSO-d₆) δ 4.54 (s, 2H); 7.01 (t, J=7.5 Hz, 1H); 7.32 (t,J=8.0 Hz, 2H); 7.49 (d, J=7.8 Hz, 2H); 7.57–7.62 (m, 2H); 7.68–7.74 (m,3H); 8.31 (d, J=8.8 Hz, 1H); 8.45 (s, 1H); 8.70 (s, 1H); 9.49 (s, 1H);MS (ESI(+)) m/e 378.0 (M+H)⁺.

EXAMPLE 83N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 83A 4-(4-amino-2-chlorophenyl)-1-isoindolinone

The desired product was prepared by substituting Example 54A and3-chloro-4-bromoaniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 1C,respectively, in Example 1D. MS (ESI(+) m/e 259, 261 (M+H)⁺.

EXAMPLE 83BN-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 83A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 4.21 (s,2H); 6.82 (d, J=7.5 Hz, 1H); 7.17 (t, J=7.5 Hz, 1H); 7.24 (dt, J=9.0,1.4 Hz, 1H); 7.32 (s, 1H); 7.38–7.39 (m, 2H); 7.50 (dd, J=7.5, 1.2 Hz,1H); 7.58 (t, J=7.5 Hz, 1H); 7.71 (dd, J=7.5, 1.4 Hz, 1H); 7.87 (d,J=2.0 Hz, 1H); 8.60 (s, 1H); 8.73 (s, 1H); 8.98 (s, 1H); MS (ESI(+)) m/e392.0 (M+H)⁺.

EXAMPLE 84N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 83A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.22 (s, 2H); 7.03–7.07 (m, 1H);7.31–7.33 (m, 2H); 7.41 (s, 2H); 7.50 (dd, J=7.5, 1.4 Hz, 1H); 7.58 (t,J=7.5 Hz, 1H); 7.70–7.73 (m, 2H); 7.86 (s, 1H); 8.60 (s, 1H); 9.04 (s,1H); 9.10 (s, 1H); MS (ESI(+)) m/e 411.9 (M+H)⁺.

EXAMPLE 85N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isbindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 83A for Example1D and 3-trifluoromethylphenyl isocyanate for 3-methylphenyl isocyanatein Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.22 (s, 2H); 7.33 (d, J=7.5Hz, 1H); 7.41 (d, J=8.1 Hz, 1H); 7.44 (dd, J=8.5, 1.7 Hz, 1H); 7.51 (dd,J=7.6, 1.4 Hz, 1H); 7.52 (d, J=8.1 Hz, 1H); 7.58 (t, J=7.5 Hz, 1H); 7.63(d, J=9.1 Hz, 1H); 7.72 (dd, J=7.5, 1.0 Hz, 1H); 7.88 (d, J=1.4 Hz, 1H);8.03 (s, 1H); 8.60 (s, 1H); 9.43 (s, 1H); 9.49 (s, 1H); MS (ESI(+)) m/e446.0 (M+H)⁺.

EXAMPLE 86N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 83A for Example1D and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.21 (s, 2H);7.42–7.46 (m, 3H); 7.50 (dd, J=7.5, 1.0 Hz, 1H); 7.58 (t, J=7.5 Hz, 1H);7.65–7.70 (m, 1H); 7.71 (dd, J=7.5, 1.4 Hz, 1H); 7.86 (t, J=1.4 Hz, 1H);8.01 (dd, J=6.3, 2.6 Hz, 1H); 8.60 (s, 1H); 9.16 (s, 1H); 9.20 (s, 1H);MS (ESI(+)) m/e 464.0 (M+H)⁺.

EXAMPLE 87N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 83A for Example1D and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.24 (s, 6H); 4.21 (s, 2H); 6.64(s, 1H); 7.09 (s, 2H); 7.35 (dd, J=8.5, 1.7 Hz, 1H); 7.40 (d, J=8.1 Hz,1H); 7.50 (dd, J=7.6, 1.2 Hz, 1H); 7.58 (t, J=7.5 Hz, 1H); 7.71 (dd,J=7.5, 1.0 Hz, 1H); 7.88 (d, J=1.7 Hz, 1H); 8.60 (s, 1H); 8.64 (s, 1H);8.95 (s, 1H); MS (ESI(+)) m/e 406.0 (M+H)⁺.

EXAMPLE 88N-(3-chlorophenyl)-N′-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]ureaEXAMPLE 88A 4-(4-amino-2-fluorophenyl)-1-isoindolinone

The desired product was prepared by substituting Example 54A and3-fluoro-4-bromoaniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 1C,respectively, in Example 1D. MS (ESI(+) m/e 243 (M+H)⁺.

EXAMPLE 88N-(3-chlorophenyl)-N′-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 88A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.55 (s, 2H); 7.06 (ddd, J=7.8,2.0, 1.0 Hz, 1H); 7.26 (ddd, J=8.1, 2.0, 1.0 Hz, 1H); 7.33 (t, J=7.8 Hz,1H); 7.43 (dd, J=8.7, 1.9 Hz, 1H); 7.58 (m, 2H); 7.68 (m, 2H); 7.75 (t,J=1.9 Hz, 1H); 8.25 (t, J=8.7 Hz, 1H); 8.69 (s, 1H); 8.75 (d, J=2.4 Hz,1H); 9.31 (s, 1H); MS (ESI(−)) m/e 394.0 (M−H)⁻.

EXAMPLE 89N-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 88A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 4.55 (s,2H); 6.82 (d, J=6.8 Hz, 1H); 7.18 (t, J=7.8 Hz, 1H); 7.25 (d, J=8.8 Hz,1H); 7.31 (s, 1H); 7.42 (dd, J=8.7, 1.9 Hz, 1H); 7.54–7.61 (m, 2H);7.67–7.70 (m, 2H); 8.29 (t, J=8.7 Hz, 1H); 8.67–8.69 (m, J=5.1 Hz, 2H);9.04 (s, 1H); MS (ESI(+)) m/e 376.1 (M+H)⁺.

EXAMPLE 90N-(3,5-dimethylphenyl)-N′-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 88A for Example1D and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 6H); 4.55 (s, 2H); 6.65(s, 1H); 7.09 (s, 2H); 7.41 (dd, J=8.5, 1.7 Hz, 1H); 7.56 (dd, J=12.9,1.7 Hz, 1H); 7.58 (d, J=15.0 Hz, 1H); 7.67–7.70 (m, 2H); 8.29 (t, J=8.7Hz, 1H); 8.66 (d, J=2.7 Hz, 1H); 8.68 (s, 1H); 8.97 (s, 1H); MS (ESI(+))m/e 390.1 (M+H)⁺.

EXAMPLE 91N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]ureaEXAMPLE 91A 4-[4-amino-3-(trifluoromethyl)phenyl]-1-isoindolinone

The desired product was prepared by substituting Example 54A and2-trifluoromethyl-4-bromoaniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 1C,respectively, in Example 1D. MS (ESI(+) m/e 293 (M+H)⁺.

EXAMPLE 91BN-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 91A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 4.54 (s,2H); 6.83 (d, J=7.7 Hz, 1H); 7.19 (t, J=7.7 Hz, 1H); 7.24–7.27 (m, 1H);7.32 (s, 1H); 7.62 (t, J=7.7 Hz, 1H); 7.71–7.75 (m, 2H); 7.85 (d, J=2.0Hz, 1H); 7.92 (dd, J=8.3, 1.9 Hz, 1H); 8.12 (d, J=8.8 Hz, 1H); 8.17 (s,1H); 8.69 (s, 1H); 9.39 (s, 1H); MS (ESI(+)) m/e 426.1 (M+H)⁺.

EXAMPLE 92N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 91A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 4.54 (s, 2H); 7.06 (ddd, J=7.7,2.1, 1.4 Hz, 1H); 7.26 (ddd, J=8.1, 2.0, 1.4 Hz, 1H); 7.34 (t, J=8.1 Hz,1H); 7.62 (t, J=7.5 Hz, 1H); 7.71–7.76 (m, 3H); 7.86 (d, J=2.0 Hz, 1H);7.93 (dd, J=8.5, 2.0 Hz, 1H); 8.09 (d, J=8.5 Hz, 1H); 8.25 (s, 1H); 8.69(s, 1H); 9.63 (s, 1H); MS (ESI(+)) m/e 446.0 (M+H)⁺.

EXAMPLE 93N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]ureaEXAMPLE 93A4-(4-Amino-3-trifluoromethyl-phenyl-2,3-dihydro-isoindol-1-one

The desired product was prepared by substituting Example 54A and3-trifluoromethyl-4-bromoaniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 1C,respectively, in Example 1D. MS (ESI(+)) m/e 293 (M+H)⁺.

EXAMPLE 93BN-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 93A for Example1D and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 3.95 (br. s, 1H);4.22 (br. s, 1H); 7.42–7.46 (m, 3H); 7.55 (t, J=7.5 Hz, 1H); 7.68–7.74(m, 3H); 8.02 (dd, J=6.4, 2.7 Hz, 1H); 8.12 (d, J=2.0 Hz, 1H); 8.59 (s,1H); 9.22 (s, 1H); 9.30 (s, 1H); MS (ESI(+)) m/e 498.0 (M+H)⁺.

EXAMPLE 94N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 91A for Example1D and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 6H); 4.54 (s, 2H); 6.66(s, 1H); 7.10 (s, 2H); 7.62 (t, J=7.5 Hz, 1H); 7.72 (dd, J=4.4, 1.0 Hz,1H); 7.74 (dd, J=4.0, 1.4 Hz, 1H); 7.85 (d, J=2.0 Hz, 1H); 7.91 (dd,J=8.5, 1.7 Hz, 1H); 8.12 (d, J=8.5 Hz, 1H); 8.16 (s, 1H); 8.71 (s, 1H);9.33 (s, 1H); MS (ESI(+)) m/e 440.1 (M+H)⁺.

EXAMPLE 95N-(3-chlorophenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 93A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 3.95 (br. s, 1H); 4.22 (br. s,1H); 7.02–7.09 (m, 1H); 7.29–7.35 (m, 2H); 7.42–7.45 (m, 2H); 7.55 (t,J=7.6 Hz, 1H); 7.68 (dd, J=8.1, 2.0 Hz, 1H); 7.71–7.74 (m, 2H); 8.13 (d,J=2.4 Hz, 1H); 8.59 (s, 1H); 9.13 (s, 1H); 9.31 (s, 1H); MS (ESI(+)) m/e446.1 (M+H)⁺.

EXAMPLE 96N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 93A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 3.95 (br. s,1H); 4.21 (br. s, 1H); 6.82 (d, J=7.1 Hz, 1H); 7.18 (t, J=7.5 Hz, 1H);7.25 (d, J=8.5 Hz, 1H); 7.34 (s, 1H); 7.41–7.44 (m, 2H); 7.55 (t, J=7.5Hz, 1H); 7.65 (dd, J=8.3, 1.9 Hz, 1H); 7.72 (dd, J=7.5, 1.0 Hz, 1H);8.14 (d, J=2.4 Hz, 1H); 8.59 (s, 1H); 8.77 (s, 1H); 9.14 (s, 1H); MS(ESI(+)) m/e 426.1 (M+H)⁺.

EXAMPLE 97N-(3,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 93A for Example1D and 3,4-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.17 (s, 3H); 2.20 (br. s, 3H);3.94 (br. s, 1H); 4.21 (s, 1H); 7.05 (d, J=8.1 Hz, 1H); 7.19 (dd, J=8.1,2.4 Hz, 1H); 7.27 (d, J=1.7 Hz, 1H); 7.40–7.44 (m, 2H); 7.55 (t, J=7.5Hz, 1H); 7.64 (dd, J=8.3, 1.9 Hz, 1H); 7.72 (dd, J=7.5, 1.0 Hz, 1H);8.13 (d, J=2.4 Hz, 1H); 8.59 (s, 1H); 8.66 (s, 1H); 9.10 (s, 1H); MS(ESI(+)) m/e 440.2 (M+H)⁺.

EXAMPLE 98N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 93A for Example1D and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 6H); 3.95 (br. s, 1H);4.22 (br. s, 1H); 6.65 (s, 1H); 7.11 (s, 2H); 7.40–7.44 (m, 2H); 7.55(t, J=7.5 Hz, 1H); 7.63 (dd, J=8.5, 2.0 Hz, 1H); 7.72 (dd, J=7.5, 1.0Hz, 1H); 8.15 (d, J=2.4 Hz, 1H); 8.59 (s, 1H); 8.67 (s, 1H); 9.11 (s,1H); MS (ESI(+)) m/e 440.1 (M+H)⁺.

EXAMPLE 99N-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 99A 4-(4-amino-3-ethylphenyl)-1-isoindolinone

The desired product was prepared by substituting Example 54A and2-ethyl-4-bromoaniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 1C,respectively, in Example 1D. MS (ESI(+) m/e 253 (M+H)⁺.

EXAMPLE 99BN-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 99A for Example1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, J=7.5 Hz, 3H);2.29 (s, 3H); 2.69 (q, J=7.5 Hz, 2H); 4.53 (s, 2H); 6.80 (d, J=7.1 Hz,1H); 7.17 (t, J=7.8 Hz, 1H); 7.25 (d, J=8.1 Hz, 1H); 7.33 (s, 1H);7.40–7.44 (m, 2H); 7.55–7.60 (m, 1H); 7.65–7.67 (m, 2H); 7.97–8.00 (m,2H); 8.65 (s, 1H); 9.02 (s, 1H); MS (ESI(+)) m/e 386.1 (M+H)⁺.

EXAMPLE 100N-(3-chlorophenyl)-N′-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 99A for Example1D and 3-chlorophenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, J=7.5 Hz, 3H); 2.69 (q,J=7.5 Hz, 2H); 4.53 (s, 2H); 7.03 (ddd, J=7.5, 2.1, 1.2 Hz, 1H); 7.25(dt, J=8.5, 1.5 Hz, 1H); 7.32 (t, J=8.1 Hz, 1H); 7.42–7.45 (m, 2H); 7.58(dd, J=8.3, 6.3 Hz, 1H); 7.65–7.68 (m, 2H); 7.77 (t, J=2.0 Hz, 1H); 7.94(d, J=8.5 Hz, 1H); 8.09 (s, 1H); 8.65 (s, 1H); 9.28 (s, 1H); MS (ESI(−))m/e 404.1 (M−H)⁻.

EXAMPLE 101N-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 99A for Example1D and 4-fluoro-3-trifluoromethylphenyl isocyanate for 3-methylphenylisocyanate in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, J=7.6 Hz,3H); 2.69 (q, J=7.6 Hz, 2H); 4.53 (s, 2H); 7.42–7.48 (m, 3H); 7.56–7.68(m, 4H); 7.91 (d, J=8.1 Hz, 1H); 8.03 (dd, J=6.6, 2.6 Hz, 1H); 8.12 (s,1H); 8.66 (s, 1H); 9.41 (s, 1H); MS (ESI(+)) m/e 458.1 (M+H)⁺.

EXAMPLE 102N-(3,5-dimethylphenyl)-N′-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 99A for Example1D and 3,5-dimethylphenyl isocyanate for 3-methylphenyl isocyanate inExample 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (t, J=7.5 Hz, 3H); 2.24 (s,6H); 2.69 (q, J=7.5 Hz, 2H); 4.53 (s, 2H); 6.62 (s, 1H); 7.10 (s, 2H);7.40–7.43 (m, 2H); 7.55–7.60 (m, 1H); 7.64–7.67 (m, 2H); 7.97–7.99 (m,2H); 8.65 (s, 1H); 8.95 (s, 1H); MS (ESI(+)) m/e 400.1 (M+H)⁺.

EXAMPLE 103 4-(2-anilino-1H-benzimidazol-5-yl)-1-isoindolinone EXAMPLE103A 5-bromo-N-phenyl-1H-benzimidazol-2-amine

Aniline (0.49 mL, 5.4 mmol) was added dropwise to a 0° C. solution ofthiocarbonyldiimidazole(1.02 g, 5.7 mmol) in pyridine (20 mL). Theresulting mixture was stirred at 0° C. for 1.5 hours, treated with2-amino-4-bromoaniline (1 g, 5.3 mmol), stirred overnight at roomtemperature, then treated with EDCI (1.23 g, 6.4 mmol) and heated to 50°C. for 24 hours. The reaction was concentrated and the residue waspurified by silica gel chromatography eluting with 20–75% ethylacetate/hexanes to give 375 mg (25%) of the desired product. MS (ESI(+))m/e 288 (M+H)⁺.

EXAMPLE 103B 4-(2-anilino-1H-benzimidazol-5-yl)-1-isoindolinone

The desired product was prepared by substituting Example 54A and Example103A for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline andExample 1C, respectively, in Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ4.52 (d, J=3.4 Hz, 2H); 6.91–6.96 (m, 1H); 7.19–7.49 (m, 5H); 7.59 (dd,J=7.1, 2.4 Hz, 1H); 7.63–7.68 (m, 2H); 7.77 (d, J=8.5 Hz, 2H); 8.62 (d,J=6.4 Hz, 1H); 9.48 (d, J=2.4 Hz, 1H); 10.97 (app d, J=20.0 Hz, 1H); MS(ESI(−)) m/e 341.1 (M−H)⁻.

EXAMPLE 104N-{4-[6-(2-methoxyethoxy)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]phenyl}-N′-(3-methylphenyl)ureaEXAMPLE 104A 4-bromo-6-methoxy-1-isoindolinone

The desired product was prepared by substituting methyl3-bromo-5-methoxy-2-methylbenzoate (prepared according to the proceduredescribed in J. Am. Chem. Soc. 1967, 1695–1704) for methyl3-bromo-2-methylbenzoate in Examples 1B-C. MS (ESI(+)) m/e 242, 244(M+H)⁺.

EXAMPLE 104B 4-bromo-6-hydroxy-1-isoindolinone

A −78° C. suspension of Example 104A (100 mg, 0.41 mmol) indichloromethane (13 mL) was treated dropwise with 1M BBr₃ indichloromethane (1.2 mL, 1.2 mmol), stirred at −78° C. for 1 hour, andstirred at room temperature for 2 hours. The mixture was treated withadditional 1M BBr₃ in dichloromethnae (0.8 mL), heated to refluxovernight, then cooled to room temperature, and partitioned betweenwater and ethyl acetate. The organic phase was dried (Na₂SO₄), filtered,and concentrated to give 91 mg (97%) of the desired product. MS (ESI(−))m/226, 228 (M−H)⁻.

EXAMPLE 104C 4-bromo-6-(2-methoxyethoxy)-1-isoindolinone

A mixture of Example 104B (100 mg, 0.44 mmol), Cs₂CO₃ (163 mg, 0.5 mmol)and 2-bromoethyl methyl ether (0.045 mL, 0.46 mmol) in DMF (2.2 mL) waswarmed to 60° C. for 4 hours, stirred at room temperature overnight, andpartitioned between water and ethyl acetate. The organic phase was dried(Na₂SO₄), filtered, and concentrated to give 128 mg of the desiredproduct. MS (ESI(+)) m/e 286,288 (M+H)⁺.

EXAMPLE 104DN-{4-[6-(2-methoxyethoxy)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 104C forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H); 3.33 (s, 3H); 3.68–3.71(m, 2H); 4.21–4.24 (m, 2H); 4.44 (s, 2H); 6.80 (d, J=7.8 Hz, 1H);7.14–7.16 (m, 2H); 7.19 (d, J=2.4 Hz, 1H); 7.25 (d, J=8.5 Hz, 1H); 7.31(s, 1H); 7.56 (s, 4H); 8.65 (s, 2H); 8.82 (s, 1H); MS (ESI(+)) m/e 432.1(M+H)⁺.

EXAMPLE 105({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}oxy)aceticacid EXAMPLE 105A Tert-butyl[(7-bromo-3-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]acetate

A mixture of Example 104B (103 mg, 0.45 mmol), Cs₂CO₃ (164 mg, 0.5 mmol)and t-butyl bromoacetate (0.075 mL, 0.5 mmol) in DMF (2.2 mL) wasstirred overnight at room temperature, diluted with water, and filtered.The filter cake was dried to give 154 mg (45%) of the desired product.MS (ESI(+)) m/e 342,344 (M+H)⁺.

EXAMPLE 105B Tert-butyl({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}oxy)acetate

The desired product was prepared by substituting Example 105A forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. MS (ESI(+)) m/e 486 (M+H)⁺.

EXAMPLE 105C({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}oxy)aceticacid

A solution of Example 105B (70 mg, 0.14 mmol) in TFA (4 mL) was stirredat room temperature for 4 hours, then concentrated to give the desiredproduct. ¹H NMR (500 MHz, DMSO-d₆) δ 2.29 (s, 3H); 4.44 (s, 2H); 4.83(s, 2H); 6.80 (d, J=7.7 Hz, 1H); 7.08 (d, J=2.4 Hz, 1H); 7.17 (t, J=7.7Hz, 1H); 7.20 (d, J=2.4 Hz, 1H); 7.25 (d, J=8.7 Hz, 1H); 7.31 (s, 1H);7.56 (m, 4H); 8.65 (s, 1H); 8.64 (s, 1H); 8.82 (s, 1H), 12.45–13.70 (br.s, 1H); MS (ESI(−)) m/e 430.1 (M−H)⁻.

EXAMPLE 106N-[4-(7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 106A Methyl 6-amino-3-bromo-2-methylbenzoate

A −20° C. solution of methyl 3-bromo-2-methylbenzoate (10 g, 43.7 mmol)in concentrated H₂SO₄ (100 mL) was treated dropwise with a solution ofconcentrated HNO₃ (2.75 μL) in concentrated H₂SO₄ (50 mL) at a rate thatmaintained the temperature below −15° C. The reaction was then stirredat 0° C. for 30 minutes, poured into ice, and extracted with diethylether. The extract was washed with aqueous NaHCO₃ and brine, dried(Na₂SO₄), filtered, and concentrated to give 9.32 g of the nitratedproduct. The crude product was added to a solution of SnCl₂ (32.2 g, 170mmol) in concentrated HCl (34 mL) and methanol (52 mL) and the resultingsuspension was stirred at room temperature for 4 hours. The resultingsolution was concentrated, adjusted to pH 7 with aqueous NaOH, andfiltered through diatomaceous earth (Celite®). The pad was washed withdiethyl ether and dichloromethane and the combined filtrates wereconcentrated. The concentrate was purified by silica gel chromatographywith 10–20% ethyl acetate/hexanes to give 3.59 g of the desired product.MS (ESI(−)) m/e 243 (M−H)⁻.

EXAMPLE 106B Methyl 3-bromo-6-hydroxy-2-methylbenzoate

A 0° C. suspension of Example 106A (1 g, 4.1 mmol) in water (6 mL) wastreated dropwise with a solution of NaNO₂ (285 mg) in water (1.25 mL),stirred at 0° C. for 15 minutes, then added slowly to a 90° C. solutionof concentrated H₂SO₄ (4 mL) in water (4 mL). The reaction was stirredat 90° C. for 45 minutes, cooled to room temperature, and extractedthree times with diethyl ether. The combined extracts were washed withaqueous NaHCO₃ and brine, dried (MgSO₄), filtered, and concentrated togive 0.87 g of the desired product. MS (ESI(−)) m/e 226 (M−H)⁻.

EXAMPLE 106C Methyl 6-(acetyloxy)-3-bromo-2-methylbenzoate

A solution of Example 106B (1.05 g, 4.3 mmol) in pyridine (3 mL) wastreated with acetic anhydride (0.82 mL, 8.6 mmol), stirred at roomtemperature for 2 hours, and partitioned between ethyl acetate and 2NHCl. The organic phase was washed sequentially with aqueous NaHCO₃,water, and brine, dried (MgSO₄), filtered, and concentrated to give 1.19g (97% yield) of the desired product. MS (ESI(+)) m/e 304, 306 (M+H)⁺.

EXAMPLE 106D 4-bromo-7-hydroxy-1-isoindolinone

The desired product was prepared by substituting Example 106C forExample 1A in Examples 1B and 1C. MS (ESI(+)) m/e 226,228 (M+H)⁺.

EXAMPLE 106EN-[4-(7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 106D forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H); 4.49 (s, 2H); 6.80 (d,J=7.7 Hz, 1H); 6.90 (d, J=8.5 Hz, 1H); 7.16 (t, J=7.7 Hz, 1H); 7.24 (d,J=8.8 Hz, 1H); 7.30 (s, 1H); 7.44–7.55 (m, 6H); 8.59 (d, J=7.1 Hz, 1H);8.74 (s, 1H); 9.47 (s, 1H); MS (ESI(+)) m/e 374.1 (M+H)⁺.

EXAMPLE 107N-[4-(7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 107A 4-bromo-7-methoxy-1-isoindolinone

A solution of Example 106D (103 mg, 0.45 mmol) in DMF (4 mL) was treatedwith Cs₂CO₃ (162 mg, 0.5 mmol) and methyl iodide (0.03 mL, 0.48 mmol),stirred at room temperature for 3 hours, then poured into water. Theresulting precipitate was filtered to give 76 mg (70%) of the desiredproduct. MS (ESI(+)) m/e 242,244 (M+H)⁺.

EXAMPLE 107BN-[4-(7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 107A forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H); 3.87 (s, 3H); 4.39 (s,2H); 6.79 (d, J=7.5 Hz, 1H); 7.11 (d, J=8.5 Hz, 1H); 7.16 (t, J=7.8 Hz,1H); 7.24 (d, J=8.5 Hz, 1H); 7.31 (s, 1H); 7.45 (d, J=8.8 Hz, 2H); 7.54(app. dd, J=8.8, 2.4 Hz, 3H); 8.29 (s, 1H); 8.63 (s, 1H); 8.77 (s, 1H);MS (DCI) m/e 388.2 (M+H)⁺.

EXAMPLE 108 Sodium({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetateEXAMPLE 108A Tert-butyl[(7-bromo-3-oxo-2,3-dihydro-1H-isoindol-4-yl)oxy]acetate

The desired product was prepared by substituting Example 106D forExample 104B in Example 105A. MS (DCI) m/e 342, 344 (M+H)⁺.

EXAMPLE 108B Sodium({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)acetate

The desired product was prepared by substituting Example 108A forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline andsubstituting toluene for methanol in Example 1D. ¹H NMR (300 MHz,DMSO-d₆) δ 2.27 (s, 3H); 4.39 (s, 2H); 4.44 (s, 2H); 6.74 (d, J=7.7 Hz,1H); 6.97 (d, J=8.8 Hz, 1H); 7.12 (t, J=7.7 Hz, 1H); 7.29 (d, J=8.8 Hz,2H); 7.34 (d, J=9.2 Hz, 2H); 7.36 (d, J=8.5 Hz, 1H); 7.43 (d, J=8.8 Hz,2H); 8.35 (s, 1H); 10.23 (s, 1H); 10.35 (s, 1H); MS (ESI(+)) m/e 432.1(M+H)⁺.

EXAMPLE 109N-{4-[7-(2-methoxyethoxy)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 106D forExample 104B in Examples 104C and 104D. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28(s, 3H); 3.36 (s, 3H); 3.69–3.72 (m, 2H); 4.25 (dd, J=5.6, 3.9 Hz, 2H);4.39 (s, 2H); 6.79 (d, J=7.1 Hz, 1H); 7.11 (d, J=8.5 Hz, 1H); 7.16 (t,J=7.8 Hz, 1H); 7.24 (d, J=8.5 Hz, 1H); 7.31 (s, 1H); 7.45 (d, J=8.8 Hz,2H); 7.52 (d, J=8.5 Hz, 1H); 7.53 (d, J=8.8 Hz, 2H); 8.32 (s, 1H); 8.63(s, 1H); 8.77 (s, 1H); MS (ESI(+)) m/e 432.1 (M+H)⁺.

EXAMPLE 110N-[4-(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)ureaEXAMPLE 110A 4-bromo-2-methyl-1-isoindolinone

A solution of Example 1B (1 g, 3.25 mmol), methylamine hydrochloride(1.1 g, 16.2 mL) and triethylamine (2.2 mL, 16.2 mmol) in methanol (16mL) was refluxed for 10 hours, cooled to room temperature, concentratedto ¼ volume, and partitioned between saturated NH₄Cl and ethyl acetate.The aqueous phase was extracted with ethyl acetate and the combinedorganic phases were washed with brine, dried (MgSO₄), filtered, andconcentrated to give 707 mg of the desired product. MS (ESI(+)) m/e 226(M+H)⁺.

EXAMPLE 110BN-[4-(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 110A forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline andsubstituting toluene for methanol in Example 1D. ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H); 3.09 (s, 3H); 4.62 (s, 2H); 6.80 (d, J=7.5 Hz,1H); 7.17 (t, J=7.5 Hz, 1H); 7.25 (d, J=8.5 Hz, 1H); 7.31 (s, 1H);7.52–7.66 (m, 7H); 8.64 (s, 1H); 8.82 (s, 1H); MS (ESI(+)) m/e 358.1(M+H)⁺.

EXAMPLE 111 Benzyl7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamateEXAMPLE 111A Methyl5-{[(benzyloxy)carbonyl]amino}-2-methyl-3-nitrobenzoate

A 0° C. solution of methyl 5-amino-2-methyl-3-nitrobenzoate (1 g, 4.76mmol, prepared according to the procedure described in J.Med.Chem. 1984,27, 386) and diisopropylethylamine (0.91 mL, 5.24 mmol) in THF (24 mL)was treated with benzyl chloroformate (0.65 mL, 5.34 mmol), stirred at0° C. for 30 minutes, warmed to room temperature for 2 hours, pouredinto water, and extracted twice with ethyl acetate. The combinedextracts were washed with brine, dried (MgSO₄), filtered, andconcentrated to give 1.7 g of the desired product. MS (ESI(−)) m/e 343(M−H)⁻.

EXAMPLE 111B Methyl5-{[(benzyloxy)carbonyl]amino}-3-iodo-2-methylbenzoate

A suspension of iron powder (0.83 g, 14.8 mmol) and ammonium chloride(1.33 g, 24.7 mmol) in water was treated dropwise with a suspension ofExample 111A (1.7 g, 4.94 mmol) in ethanol, stirred at 80° C. for 6hours, cooled to room temperature, and filtered through diatomaceousearth (Celite®). The pad was washed with warm methanol and the filtratewas concentrated. The concentrate was partitioned between ethyl acetateand water. The extract was washed with brine, dried (MgSO₄), filtered,and concentrated to give 1.49 g of the intermediate amine. The crudeproduct was dissolved in DMF (10 mL), cooled to 0° C., and treateddropwise with 6M HCl (2.4 mL) followed by a solution of NaNO₂ (0.327 g,4.75 mmol) in water (5 mL). The solution was stirred at 0° C. for 30minutes, treated portionwise with KI (788 mg, 4.75 mmol), diluted withDMF (10 μL), stirred at 0° C. for 2 hours, warmed to room temperaturefor 30 minutes, and extracted with diethyl ether. The extract was washedwith aqueous 10% sodium thiosulfate, water, and brine, dried (MgSO₄),filtered, and concentrated. The residue was purified by silica gelchromatography with dichloromethane to give 0.86 g of the desiredproduct. MS (ESI(+)) m/e 443 (M+NH₄)⁺.

EXAMPLE 111C Benzyl 7-iodo-3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate

The desired product was prepared by substituting Example 111B forExample 1A in Examples 1B and 1C. MS (ESI(+)) m/e 426 (M+NH₄)⁺.

EXAMPLE 111D Benzyl7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate

The desired product was prepared by substituting Example 111C forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. ¹H NMR (300 MHz, DMSO-d₆) d 2.28 (s, 3H); 4.44 (s, 2H); 5.19 (s,2H); 6.80 (d, J=6.8 Hz, 1H); 7.16 (dd, J=8.1, 7.5 Hz, 1H); 7.23–7.26 (m,1H); 7.31 (s, 1H); 7.35–7.50 (m, 7H); 7.57 (d, J=8.5 Hz, 2H); 7.72 (d,J=1.7 Hz, 1H); 7.81 (s, 1H); 8.64 (s, 2H); 8.81 (s, 1H); 10.05 (s, 1H);MS (ESI(−)) m/e 505.0 (M−H)⁻.

EXAMPLE 112N-(3-methylphenyl)-N′-[3-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting 3-aminophenylboronicacid for 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)aniline inExamples ID and 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H); 4.51 (s,2H); 6.79 (d, J=7.5 Hz, 1H); 7.16 (t, J=7.6 Hz, 1H); 7.21–7.26 (m, 2H);7.31 (s, 1H); 7.40–7.42 (m, 2H); 7.61 (t, J=7.5 Hz, 1H); 7.67 (dd,J=7.5, 1.7 Hz, 1H); 7.70 (dd, J=7.1, 1.4 Hz, 1H); 7.78 (s, 1H); 8.67 (s,1H); 8.70 (s, 1H); 8.80 (s, 1H); MS (ESI(+)) m/e 358.1 (M+H)⁺.

EXAMPLE 113N-[4-(6-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 104A forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H); 3.87 (s, 3H); 4.43 (s,2H); 6.80 (d, J=7.5 Hz, 1H); 7.14–7.16 (m, 2H); 7.19 (d, J=2.4 Hz, 1H);7.25 (d, J=9.2 Hz, 1H); 7.31 (s, 1H); 7.56 (app. s, 4H); 8.64 (app. s,2H); 8.81 (s, 1H); MS (ESI(+)) m/e 388.1 (M+H)⁺.

EXAMPLE 114N-(3-methylphenyl)-N′-(4-{7-[3-(4-morpholinyl)propoxy]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}phenyl)ureaEXAMPLE 114A 4-bromo-7-(3-chloropropoxy)-1-isoindolinone

A suspension of Example 106D (250 mg, 1.1 mmol), 3-chloropropanol (0.095mL, 1.1 mmol), and triphenylphosphine (350 mg, 1.3 mmol) indichloromethane (5 mL) at 0° C., was treated dropwise with DEAD (0.21mL, 1.3 mmol) over 10 minutes. The resulting mixture was stirred at 0°C. for 1 hour, warmed to room temperature overnight, and concentrated.The residue was purified by silica gel chromatography with 50 to 60%ethyl acetate/hexanes to give 227 mg of the desired product which wascontaminated with triphenylphosphine oxide. MS (ESI(+)) m/e 304,306(M+H)⁺.

EXAMPLE 114B 4-bromo-7-[3-(4-morpholinyl)propoxy]-1-isoindolinone

A solution of Example 114A (227 mg, 0.75 mmol), morpholine (0.33 mL, 3.8mmol), and potassium iodide (70 mg, 0.42 mmol) in DMF (3 mL) was heatedto 100° C. overnight in a sealed reaction vessel, poured into water, andfiltered. The filtrate was extracted with ethyl acetate and the extractwas washed with brine, dried (Na₂SO₄), filtered, and concentrated. Theconcentrate was purified by silica gel chromatography with 5 to 7%methanol/dichloromethane containing 1% triethylamine to give 130 mg ofthe desired product. MS (ESI(+)) m/e 355,357 (M+H)⁺.

EXAMPLE 114CN-(3-methylphenyl)-N′-(4-{7-[3-(4-morpholinyl)propoxy]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}phenyl)urea

The desired product was prepared by substituting Example 114B forExample 1C andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example1D. ¹H NMR (300 MHz, DMSO-d₆) δ 1.90 (m, 2H); 2.28 (s, 3H); 2.37 (m,4H); 2.48 (t, J=7.5 Hz, 2H); 3.57 (m, 4H); 4.15 (t, J=6.1 Hz, 2H); 4.38(s, 2H); 6.79 (d, J=7.5 Hz, 1H); 7.10 (d, J=8.8 Hz, 1H); 7.16 (t, J=7.5Hz, 1H); 7.24 (d, J=8.1 Hz, 1H); 7.31 (s, 1H); 7.45 (d, J=8.8 Hz, 2H);7.52 (m, 3H); 8.28 (s, 1H); 8.65 (s, 1H); 8.79 (s, 1H). MS (ESI(+)) m/e501.2 (M+H)⁺.

EXAMPLE 115N-(3-methylphenyl)-2-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]acetamideEXAMPLE 115A 2-(4-bromophenyl)-N-(3-methylphenyl)acetamide

A solution of 4-bromophenylacetic acid (502 mg, 2.33 mmol), m-toluidine(0.25 mL, 2.33 mmol), HOBT (350 mg, 2.59 mmol), and N-methylmorpholine(0.51 mL, 4.64 mmol) in DMF (10 mL) was treated with EDCI (496 mg, 2.59mmol), stirred overnight at room temperature, and poured into ice water.The resulting white precipitate was collected by filtration to give 672mg of the desired product. MS (ESI(+)) m/e 304, 306 (M+H)⁺.

EXAMPLE 115BN-(3-methylphenyl)-2-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]acetamide

The desired product was prepared by substituting Example 115A forN-(6-bromo-3-pyridinyl)-N-(3-methylphenyl)urea in Example 54B. ¹H NMR(300 MHz, DMSO-d₆) δ 2.27 (s, 3H); 3.69 (s, 2H); 4.51 (s, 2H); 6.86(d,J=7.6 Hz, 1H); 7.18 (t,J=7.6 Hz, 1H); 7.40 (d, J=8.5 Hz, 1H);7.44–7.47 (m, 3H); 7.56–7.61 (m, 3H); 7.63–7.69 (m, 2H); 8.67 (s, 1H);10.13 (s, 1H); MS (ESI(+)) m/e 357.1 (M+H)⁺.

EXAMPLE 116N-methyl-N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

A suspension of Example 1D (0.25 g, 1.1 mmol) in dioxane (3 mL) wassequentially treated with triethylamine (0.17 mL, 1.2 mmol) andtriphosgene (0.11 g, 0.37 mmol), heated to 70° C. for 2 hours, andconcentrated. The concentrate was resuspended in THF (3 mL), treatedwith N-methyltoluidine, stirred at room temperature for 18 hours, andpartitioned between water and ethyl acetate. The aqueous phase wasextracted with ethyl acetate and the combined extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by silica gel chromatography with 2% methanol/dichloromethaneto give 76 mg (20% yield) of the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.34 (s, 3H); 3.27 (s, 3H); 4.50 (s, 2H); 7.08 (d, J=7.46 Hz,1H); 7.12 (d, J=8.48 Hz, 1H); 7.17 (s, 1H); 7.31 (t, J=7.80 Hz, 1H);7.48 (d, J=8.82 Hz, 2H); 7.57 (d, J=8.82 Hz, 3H); 7.62 (d, J=3.39 Hz,1H); 7.65 (d, J=5.76 Hz, 1H); 8.24 (s, 1H); 8.64 (s, 1H). MS (ESI(+))m/e 372 (M+H)⁺.

EXAMPLE 117N-(3-chlorophenyl)-N-methyl-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting3-chloro-N-methylaniline for N-methyltoluidine in Example 116. ¹H NMR(300 MHz, DMSO-d₆) δ 3.34 (s, 3H); 4.51 (s, 2H); 7.28–7.30 (m, 1H);7.31–7.33 (m, 1H); 7.41 (d, J=8.14 Hz, 1H); 7.46 (d, J=6.78 Hz, 1H);7.51 (d, J=8.81 Hz, 2H); 7.57 (s, 1H); 7.59 (d, J=2.71 Hz, 2H); 7.63 (d,J=2.37 Hz, 1H); 7.65 (d, J=4.41 Hz, 1H); 8.60 (s, 1H); 8.67 (s, 1H). MS(ESI(−)) m/e 390 (M−H)⁻.

EXAMPLE 118N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}benzamide

The desired product was prepared by substituting benzoyl chloride foracetyl chloride in Example 4. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H);4.62 (s, 2H); 6.80 (d, J=7.12 Hz, 1H); 7.17 (t, J=7.63 Hz, 1H); 7.25 (d,J=8.48 Hz, 1H); 7.31 (s, 1H); 7.56 (s, 4H); 7.61 (d, J=8.81 Hz, 1H);7.67 (d, J=9.49 Hz, 2H); 7.71 (d, J=8.48 Hz, 1H); 7.99 (dd, J=7.97, 1.53Hz, 2H); 8.57 (d, J=8.48 Hz, 1H); 8.63 (s, 1H); 8.80 (s, 1H); 9.09 (s,1H); 11.74 (s, 1H); MS (ESI(−)) m/e 475 (M−H)⁻.

EXAMPLE 1193-(dimethylamino)-N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}benzamide

The desired product was prepared by substituting 3-dimethylaminobenzoylchloride for acetyl chloride in Example 4. ¹H NMR (300 MHz, DMSO-d₆) δ2.29 (s, 3H); 3.00 (s, 6H); 4.61 (s, 2H); 6.80 (d, J=7.12 Hz, 1H); 7.00(dd, J=8.14, 2.37 Hz, 1H); 7.17 (t, J=7.63 Hz, 1H); 7.24 (d, J=6.78 Hz,2H); 7.31 (s, 2H); 7.40 (t, J=7.97 Hz, 1H); 7.56 (s, 4H); 7.70 (d,J=8.48 Hz, 1H); 8.56 (d, J=8.14 Hz, 1H); 8.62 (s, 1H); 8.79 (s, 1H);9.07 (s, 1H); 11.71 (s, 1H); MS (ESI(−)) m/e 518 (M−H)⁻.

EXAMPLE 120N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-1,3-thiazole-2-carboxamide

The desired product was prepared by substituting1,3-thiazole-2-carboxylic acid and Example 1D for 4-bromophenylaceticacid and m-toluidine respectively, in Example 115A. ¹H NMR (500 MHz,DMSO-d₆) δ 4.52 (s, 2H); 7.58 (t, J=7.49 Hz, 1H); 7.62 (d, J=8.42 Hz,2H); 7.67 (d, J=8.42 Hz, 2H); 7.99 (d, J=8.42 Hz, 2H); 8.12 (d, J=3.12Hz, 1H); 8.14 (d, J=3.12 Hz, 1H); 8.64 (s, 1H); 10.90 (s, 1H); MS(ESI(−)) m/e 334 (M−H)⁻.

EXAMPLE 121N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]thiourea

A solution of Example 1D (0.1 g, 0.44 mmol) in DMF (3 mL) was treatedwith m-tolylisothiocyanate (0.06 mL, 0.45 mmol), stirred at roomtemperature overnight, then cooled to 0° C., treated with water, andextracted twice with ethyl acetate. The combined extracts were washedwith brine, dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by silica gel chromatography eluting with 3%methanol/dichloromethane to give 72 mg of the desired product. ¹H NMR(300 MHz, DMSO-d₆) δ 2.30 (s, 3H); 4.53 (s, 2H); 6.96 (d, J=7.12 Hz,1H); 7.23 (t, J=7.80 Hz, 1H); 7.29 (d, J=7.80 Hz, 2H); 7.57–7.69 (m,7H); 8.68 (s, 1H); 9.84 (s, 1H); 9.88 (s, 1H); MS (ESI(−)) m/e 372(M−H)⁻.

EXAMPLE 122N-methyl-N′-(3-methylphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]ureaEXAMPLE 122A 4-[4-(methylamino)phenyl]-1-isoindolinone

The desired product was prepared by substituting 4-bromo-N-methylaniline(Tetrahedron. Lett. 1993, 34, 2115) forN-(6-bromo-3-pyridinyl)-N′-(3-methylphenyl)urea in Example 54B. MS(ESI(+)) m/e 239 (M+H)⁺.

EXAMPLE 122BN-methyl-N′-(3-methylphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 122A forExample 1D in Example 1E. ¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (s, 3H); 3.33(s, 3H); 4.55 (s, 2H); 6.78 (d, J=7.46 Hz, 1H); 7.12 (t, J=7.80 Hz, 1H);7.27 (d, J=7.80 Hz, 2H); 7.43 (d, J=8.48 Hz, 2H); 7.58–7.70 (m, 5H);8.26 (s, 1H); 8.68 (s, 1H); MS (ESI(+)) m/e 372 (M+H)⁺.

EXAMPLE 1234-(2,5-dimethoxyphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-1,3-thiazole-2-carboxamide

The desired product was prepared by substituting4-(2,5-dimethoxyphenyl)-1,3-thiazole-2-carboxylic acid and Example 1Dfor 4-bromophenylacetic acid and m-toluidine, respectively, in Example1115A. ¹H NMR (300 MHz, DMSO-d₆) δ 3.83 (s, 3H); 3.91 (s, 3H); 4.56 (s,2H); 7.00 (dd, J=8.99, 3.22 Hz, 1H); 7.13 (d, J=9.16 Hz, 1H); 7.62 (d,J=7.46 Hz, 1H); 7.65–7.73 (m, 4H); 8.02 (d, J=8.48 Hz, 2H); 8.09 (d,J=3.05 Hz, 1H); 8.47 (s, 1H); 8.68 (s, 1H); 10.78 (s, 1H); MS (ESI(−))m/e 470 (M−H)⁻.

EXAMPLE 1244-(3-bromophenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-1,3-thiazole-2-carboxamide

The desired product was prepared by substituting4-(3-bromophenyl)-1,3-thiazole-2-carboxylic acid and Example 1D for4-bromophenylacetic acid and m-toluidine, respectively, in Example 115A.¹H NMR (300 MHz, DMSO-d₆) δ 4.56 (s, 2H); 7.49 (t, J=7.80 Hz, 1H);7.58–7.64 (m, 2H); 7.67–7.72 (m, 4H); 8.02 (d, J=8.82 Hz, 2H); 8.18 (d,J=7.80 Hz, 1H); 8.45 (s, 1H); 8.67 (d, J=7.46 Hz, 2H); 10.80 (s, 1H); MS(ESI(−)) m/e 488 (M−H)⁻.

EXAMPLE 1254-(4-{[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]amino}phenyl)-1-isoindolinoneEXAMPLE 125A [4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-phenyl]-thiourea

A solution of ammonium thioisocyanate (78 mg, 1.07 mmol) in acetone (5mL) was treated with benzoyl chloride (0.118 mL, 1.07 mmol), heated toreflux for 20 minutes, removed from heat, treated with Example 1D (200mg, 0.89 mmol) and stirred at reflux for 1 hour. The resulting mixturewas poured into ice water and the precipitate filtered, washed withwater, and dried to give 295 mg of an off white solid which was added to5% aqueous NaOH solution (5 mL). The suspension was heated to 80° C. for30 minutes, cooled to room temperature, and poured onto cold 1N HCl. ThepH of the solution was adjusted to pH 8 with saturated aqueous Na₂CO₃,and the turbid mixture was filtered. The filter cake was washed withwater and dried to give 194 mg (77% yield) of the desired product. MS(ESI(−)) m/e 282 (M−H)⁻.

EXAMPLE 125B4-(4-{[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]amino}phenyl)-1-isoindolinone

A suspension of Example 125A (90 mg, 0.32 mmol) and2-bromo-1-(4-methoxy-phenyl)ethanone (73 mg, 0.32 mmol) in ethanol (3mL) was stirred at reflux for 2 hours, cooled to room temperature, andfiltered. The filter cake was washed with ethanol and dichloromethaneand dried to give 118 mg (90% yield) of the desired product as thehydrobromide salt. ¹H NMR (300 MHz, DMSO-d₆) δ 3.80 (s, 3H); 4.55 (s,2H); 7.01 (d, J=8.81 Hz, 2H); 7.21 (s, 1H); 7.58–7.64 (m, 3H); 7.66–7.69(m, 2H); 7.86 (dd, J=8.81, 7.12 Hz, 4H); 8.67 (s, 1H); 10.43 (s, 1H); MS(ESI(+)) m/e 414 (M+H)⁺.

EXAMPLE 126 4-[4-(1H-benzimidazol-2-ylamino)phenyl]-1-isoindolinonetrifluoroacetate

A 0° C. solution of thiocarbonyldiimidazole (442 mg, 2.23 mmol) inpyridine (8 mL) was treated dropwise with a solution of Example 1D (500mg, 2.23 mmol) in pyridine (8 nmL), stirred at 0° C. for 1.5 hours,warmed to room temperature, treated with 1,2-diaminobenzene (241 mg,2.68 mmol), stirred at room temperature overnight, treated with EDCI(513 mg, 2.68 mmol), heated to 50° C. overnight, and concentrated. Theresidue was partitioned between ethyl acetate/THF and water. The organicextract was dried (MgSO₄), filtered, and concentrated. The concentratewas purified by silica gel chromatography with 5%methanol/dichloromethane, then further purified by preparative HPLC on aWaters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using agradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8 minutes (10minute run time) at a flow rate of 40 mL/min to give to give 17 mg ofthe desired product. ¹H NMR (300 MHz, DMSO-d₆) δ 4.56 (s, 2H); 7.25 (d,J=3.39 Hz, 1H); 7.27 (d, J=3.05 Hz, 1H); 7.43 (d, J=3.05 Hz, 1H); 7.45(d, J=3.39 Hz, 1H); 7.62–7.26 (m, 7H); 8.71 (s, 1H); 10.95 (s, 1H);12.94 (s, 1H); MS (ESI(−)) m/e 339 (M−H)⁻.

EXAMPLE 127N-(3-methylphenyl)-N′-[5-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-thienyl]ureaEXAMPLE 127A Methyl5-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxylate

The desired product was prepared by substituting methyl5-bromo-2-thiophenecarboxylate forN-(6-bromo-3-pyridinyl)-N′-(3-methylphenyl)urea in Example 54B.R_(f)=0.45 (10% CH₃OH/CH₂Cl₂).

EXAMPLE 127B5-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxylic acid

A suspension of Example 127A (0.34 g, 1.24 mmol) in THF (30 mL) andmethanol (30 mL) was treated with 1N LiOH (10 mL), stirred at roomtemperature for 5 hours, then acidified with 1N HCl and diluted withdiethyl ether. The resulting suspension was filtered and the filter cakewas washed with water and dried to give 288 mg of the desired product.MS (ESI(−)) m/e 258 (M−H)⁻.

EXAMPLE 127CN-(3-methylphenyl)-N′-[5-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-thienyl]urea

A solution of Example 127B (70 mg, 0.27 mmol) and triethylamine (0.046mL, 0.32 mmol) in DMF (8 mL) was treated with diphenylphosphorylazide(0.072 mL, 0.32 mmol), heated to 80° C. for 2 hours, cooled to roomtemperature, and treated with 3-methylaniline (0.03 mL, 0.27 mL). Theresulting mixture was heated to 80° C. for 2 hours, cooled to roomtemperature, diluted with water, and extracted with dichloromethane andethyl acetate. The combined extracts were dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by silica gel chromatography,with 3% methanol/dichloromethane to give the desired product (13%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 4.58 (s, 2H), 6.63 (d,1H, J =4.2 Hz), 6.82 (d, 1H, J=6.9 Hz), 7.14–7.27 (m, 3H), 7.34 (s, 1H),7.48–7.58 (m, 2H), 7.75–7.79 (m, 1H), 8.73 (s, 1H), 8.77 (s, 1H), 9.86(s, 1H); MS (ESI(+)) m/e 364.0 (M+H)⁺.

EXAMPLE 128N-(3-methylphenyl)-N′-[4-(6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]ureaEXAMPLE 128A Methyl4′-amino-2-methyl-5-nitro-1,1′-biphenyl-3-carboxylate

Example 1A (20 g, 87.3 mmol) was cooled to −5° C. and treated dropwisewith H₂SO₄ (100 mL) at such a rate as to maintain the internaltemperature below 10° C. The reaction mixture was cooled to −30° C. andtreated dropwise with nitric acid (5.7 mL, 91.7 mmol) at such a rate asto maintain the internal temperature below −12° C. After the additionwas complete the reaction flask was placed in an ice bath for 30 minutesand poured onto crushed ice. The resulting suspension was extractedtwice with diethyl ether and the combined extracts were washed withaqueous NaHCO₃ and brine, dried (MgSO₄), filtered, and concentrated togive 23 g of a mixture of methyl 3-bromo-2-methyl-5-nitrobenzoate andmethyl 3-bromo-2-methyl-6-nitrobenzoate. Substitution of this mixturefor Example 1C in Example 1D followed by purification by silica gelchromatography with 10 to 40% ethyl acetate/hexanes provided the desiredproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 2.46 (s, 3H), 3.91 (s, 3H), 5.36(s, 2H), 6.67 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.1 Hz, 2H), 8.06 (d, J=2.7Hz, 1H), 8.41 (d, J=2.7 Hz, 1H).

EXAMPLE 128B Methyl4′-[(tert-butoxycarbonyl)amino]-2-methyl-5-nitro-1,1′-biphenyl-3-carboxylate

A suspension of Example 128A (1.606 g, 5.6 mmol) in THF (10 mL) wastreated with triethylamine(0.78 mL, 5.6 mmol) anddi-tert-butyldicarbonate (1.34 g, 6.17 mmol), and stirred at roomtemperature for 18 hours. The resulting precipitate was removed byfiltration and the filtrate was concentrated. The concentrate waspurified by silica gel chromatography with 20 to 30% ethylacetate/hexanes to give 1.36 g of the desired product. m.p. 131–132° C.

EXAMPLE 128C 4-(4-aminophenyl)-6-nitro-1-isoindolinone

A solution of tert-butyl4-(6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenylcarbamate (0.276 g,prepared by substituting Example 128B for Example 1A in Examples 1B and1C) in TFA (3 mL) and CH₂Cl₂ (3 mL) was stirred at room temperature for1 hour, then concentrated to give 0.085 g of the desired product. ¹H NMR(300 MHz, DMSO-d₆) δ 4.66 (s, 2H), 5.50 (s, 2H), 6.70 (d, J=8.5 Hz, 1H),7.40 (d, J=8.8 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H),9.03 (s, 1H).

EXAMPLE 128DN-(3-methylphenyl)-N′-[4-(6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea

The desired product was prepared by substituting Example 128C forExample 1D in Example 1E. MS (ESI(−)) m/e 401 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H), 4.70 (s, 2H), 6.81 (d, J=7.12 Hz, 1H), 7.17 (t,J=7.80 Hz, 1H), 7.25 (m, J=8.14 Hz, 1H), 7.32 (s, 1H), 7.65 (m, 4H),8.30 (d, J=2.03 Hz, 1H), 8.40 (d, J=2.03 Hz, 1H), 8.66 (s, 1H), 8.89 (s,1H), 9.09 (s, 1H).

EXAMPLE 129N-[4-(6-amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 128D forExample 2 in Example 3. ¹H NMR (500 MHz, DMSO-d₆) δ 2.28 (s, 3H), 4.31(s, 2H), 5.36 (s, 2H), 6.80 (d, J=7.32 Hz, 1H), 6.82 (d, J=1.83 Hz, 1H),6.86 (d, J=2.14 Hz, 1H), 7.16 (t, J=7.78 Hz, 1H), 7.25 (d, J=8.24 Hz,1H), 7.31 (s, 1H), 7.45 (d, J=8.85 Hz, 2H), 7.54 (d, J=8.54 Hz, 2H),8.40 (s, 1H), 8.69 (s, 1H), 8.84 (s, 1H); MS (ESI(+)) m/e 373 (M+H)⁺.

EXAMPLE 130N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}acetamide

The desired product was prepared by substituting Example 129 for Example3 in Example 4. MS (ESI(−)) m/e 413 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.09 (s, 3H), 2.29 (s, 3H), 4.45 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.16(t, J=7.8 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.32 (s, 1H), 7.50 (d, J=8.5Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.98 (d, J=2.0Hz, 1H), 8.65 (d, J=4.8 Hz, 2H), 8.84 (s, 1H), 10.19 (s, 1H).

It will be evident to one skilled in the art that the present inventionis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein R¹ is selectedfrom the group consisting of hydrogen and alkyl; R² is selected from thegroup consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl,carboxyalkoxy, carboxyalkyl, halo, haloalkyl, heterocyclylalkoxy,hydroxy, nitro, and —NR^(c)R^(d); and one of R³ and R⁴ A-X-R⁵ and theother is hydrogen; wherein A-X-R⁵ is drawn with its left end attached tothe parent molecular moiety; R⁵ is phenyl; A is phenyl which isoptionally substituted with one or two substituents independentlyselected from the group consisting of alkyl, halo, haloalkoxy, andhaloalkyl; and X is (CH₂)_(m)N(R^(a))C(O)N(R^(b))(CH₂)_(n), whereinR^(a) and R^(b) are hydrogen, m and n are and wherein each group isdrawn with its left end attached to A and its right end attached to R⁵.2. The compound of claim 1 wherein R² is other than hydrogen.
 3. Thecompound of claim 2 selected from the group consisting ofN-(3-methylphenyl)-N′-[4-(7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-(7-amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetamide;N²,N²-dimethyl-N¹-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}glycinamide;N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}nicotinamide;N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-phenylacetamide;2-(2-methoxyethoxy)-N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}acetamide;N-{4-[6-(2-methoxyethoxy)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]phenyl}-N′-(3-methylphenyl)urea;({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}oxy)aceticacid;N-[4-(7-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;({7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)aceticacid;N-{4-[7-(2-methoxyethoxy)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]phenyl}-N′-(3-methylphenyl)urea;benzyl7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-ylcarbamate;N-[4-(6-methoxy-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-(3-methylphenyl)-N′-(4-{7-[3-(4-morpholinyl)propoxy]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}phenyl)urea;N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}benzamide;3-(dimethylamino)-N-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}benzamide;N-(3-methylphenyl)-N′-[4-(6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-(6-amino-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;andN-{7-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}acetamide.4. The compound of claim 1 wherein R² is hydrogen.
 5. The compound ofclaim 4 selected from the group consisting ofN-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-phenylurea andN-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-phenylurea.6. The compound of claim 4 wherein R⁵ is monosubstituted.
 7. Thecompound of claim 6 wherein A is unsubstituted.
 8. The compound of claim7 selected from the group consisting ofN-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(4-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(4-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(4-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(4-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(4-bromophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-(trifluoromethoxy)phenyl]urea;N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-phenoxyphenyl)urea;N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea;N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(4-phenoxyphenyl)urea;N-[3-(benzyloxy)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-(3-ethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-cyanophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;methyl3-[({[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]amino}carbonyl)amino]benzoate;N-(3-acetylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-methylphenyl)-N′-[6-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-pyridinyl]urea;N-[4-(2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-(3-methylphenyl)-N′-[3-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-methyl-N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-chlorophenyl)-N-methyl-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-methyl-N′-(3-methylphenyl)-N-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;andN-(3-methylphenyl)-N′-[5-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-thienyl]urea.9. The compound of claim 6 wherein A is monosubstituted.
 10. Thecompound of claim 9 selected from the group consisting ofN-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-(3-chlorophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;N-(4-chlorophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-bromophenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethoxy)phenyl]urea;N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethoxy)phenyl]urea;N-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-(3-chlorophenyl)-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-(3-chlorophenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-(3-chlorophenyl)-N′-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea;N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea;N-(3-chlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;N-(3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;N-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3-methylphenyl)urea;andN-(3-chlorophenyl)-N′-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea.11. The compound of claim 1 wherein A is unsubstituted.
 12. The compoundof claim 11 selected from the group consisting ofN-(2,3-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2,3-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2,4-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2,5-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,4-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,5-dimethoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2,3-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(2,5-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,4-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,5-dichlorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-chloro-4-methoxyphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(4-bromo-3-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-chloro-4-fluorophenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3-chloro-4-methylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[2-fluoro-5-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;andN-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea.13. The compound of claim 1 wherein A is monosubstituted.
 14. Thecompound of claim 13 selected from the group consisting ofN-(3,4-dimethylphenyl)-N′-[2-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,4-dimethylphenyl)-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[2-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,4-dimethylphenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-(3,5-dimethylphenyl)-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[3-methyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[2-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea;N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;N-[3-chloro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea;N-(3,5-dimethylphenyl)-N′-[3-fluoro-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea;N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)phenyl]urea;N-(3,4-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;N-(3,5-dimethylphenyl)-N′-[4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)-3-(trifluoromethyl)phenyl]urea;N-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;andN-(3,5-dimethylphenyl)-N′-[2-ethyl-4-(1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenyl]urea.15. A pharmaceutical composition comprising a compound of claim 1 or atherapeutically acceptable salt thereof, in combination with atherapeutically acceptable carrier.